Modafinil compositions

ABSTRACT

Co-crystals and solvates of racemic, enantiomerically pure, and enantiomerically mixed modafinil are formed and several important physical properties are modulated. The solubility, dissolution, bioavailability, dose response, and stability of modafinil can be modulated to improve efficacy in pharmaceutical compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Application No.PCT/US03/27772, filed Sep. 4, 2003, which claims the benefit of U.S.application Ser. No. 10/378,956, filed Mar. 3, 2003, U.S. ProvisionalApplication No. 60/463,962, filed Apr. 18, 2003, U.S. ProvisionalApplication No. 60/451,213, filed Feb. 28, 2003, and U.S. ProvisionalApplication No. 60/487,064, filed Jul. 11, 2003. Said U.S. applicationSer. No. 10/378,956, filed Mar. 3, 2003 claims the benefit of U.S.Provisional Application No. 60/360,768, filed Mar. 1, 2002.

This application is also a continuation-in-part of U.S. application Ser.No. 10/660,202, filed Sep. 11, 2003, which claims the benefit ofPCT/US03/27772, filed Sep. 4, 2003. Said U.S. application Ser. No.10/660,202, filed Sep. 11, 2003 also claims the benefit of U.S.application Ser. No. 10/637,829, filed Aug. 8, 2003, which is adivisional of U.S. application Ser. No. 10/295,995, filed Nov. 18, 2002,which is a continuation of U.S. application Ser. No. 10/232,589, filedSep. 3, 2002, which claims the benefit of U.S. Provisional ApplicationNo. 60/406,974, filed Aug. 30, 2002, U.S. Provisional Application No.60/380,288, filed May 15, 2002, and U.S. Provisional Application No.60/356,764, filed Feb. 15, 2002. Said U.S. application Ser. No.10/660,202, filed Sep. 11, 2003, is also a continuation-in-part of U.S.application Ser. No. 10/449,307, filed May 30, 2003, which claims thebenefit of U.S. Provisional Application No. 60/463,962, filed Apr. 18,2003, U.S. Provisional Application No. 60/444,315, filed Jan. 31, 2003,U.S. Provisional Application No. 60/439,282, filed Jan. 10, 2003, andU.S. Provisional Application No. 60/384,152, filed May 31, 2002. SaidU.S. application Ser. No. 10/660,202, filed Sep. 11, 2003, is also acontinuation-in-part of U.S. application Ser. No. 10/601,092, filed Jun.20, 2003. Said U.S. application Ser. No. 10/660,202, filed Sep. 11,2003, also claims the benefit of U.S. Provisional Application No.60/451,213, filed Feb. 28, 2003, U.S. Provisional Application No.60/463,962, filed Apr. 18, 2003, and U.S. Provisional Application No.60/487,064, filed Jul. 11, 2003.

This application is also a continuation-in-part of Application No.PCT/US04/06288, filed Feb. 26, 2004, which claims the benefit of U.S.Provisional Application No. 60/451,213, filed Feb. 28, 2003, U.S.Provisional Application No. 60/487,064, filed Jul. 11, 2003, ApplicationNo. PCT/US03/27772, filed Sep. 4, 2003, U.S. application Ser. No.10/660,202, filed Sep. 11, 2003, Application No. PCT/US03/06662, filedMar. 3, 2003, U.S. Provisional Application No. 60/508,208, filed Oct. 2,2003, U.S. Provisional Application No. 60/542,752, filed Feb. 6, 2004,U.S. Provisional Application No. 60/463,962, filed Apr. 18, 2003, U.S.application Ser. No. 10/449,307, filed May 30, 2003, U.S. ProvisionalApplication No. 60/456,027, filed Mar. 18, 2003, U.S. application Ser.No. 10/601,092, filed Jun. 20, 2003, Application No. PCT/US03/19574,filed Jun. 20, 2003, and Application No. PCT/US03/41273, filed Dec. 24,2003.

This application also claims the benefit of U.S. Provisional ApplicationNo. 60/508,208, filed Oct. 2, 2003, U.S. Provisional Application No.60/542,752, filed Feb. 6, 2004, U.S. Provisional Application No.60/560,411, filed Apr. 6, 2004, U.S. Provisional Application No.60/573,412, filed May 21, 2004, U.S. Provisional Application No.60/579,176, filed Jun. 12, 2004, U.S. Provisional Application No.60/581,992, filed Jun. 22, 2004, U.S. Provisional Application No.60/586,752, filed Jul. 9, 2004, and U.S. Provisional Application No.60/588,236, filed Jul. 15, 2004.

All of the applications above, to which a benefit is claimed, are hereinincorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to API-containing compositions,pharmaceutical compositions comprising such APIs, and methods forpreparing the same.

BACKGROUND OF THE INVENTION

Active pharmaceutical ingredients (API or APIs (plural)) inpharmaceutical compositions can be prepared in a variety of differentforms. Such APIs can be prepared so as to have a variety of differentchemical forms including chemical derivatives, solvates, hydrates,co-crystals, or salts. Such APIs can also be prepared to have differentphysical forms. For example, the APIs may be amorphous, may havedifferent crystalline polymorphs, or may exist in different solvation orhydration states. By varying the form of an API, it is possible to varythe physical properties thereof. For example, crystalline polymorphstypically have different solubilities from one another, such that a morethermodynamically stable polymorph is less soluble than a lessthermodynamically stable polymorph. Pharmaceutical polymorphs can alsodiffer in properties such as shelf-life, bioavailability, morphology,vapour pressure, density, colour, and compressibility. Accordingly,variation of the crystalline state of an API is one of many ways inwhich to modulate the physical properties thereof.

It would be advantageous to have new forms of these APIs that haveimproved properties, in particular, as oral formulations. Specifically,it is desirable to identify improved forms of APIs that exhibitsignificantly improved properties including increased aqueous solubilityand stability. Further, it is desirable to improve the processability,or preparation of pharmaceutical formulations. For example, needle-likecrystal forms or habits of APIs can cause aggregation, even incompositions where the API is mixed with other substances, such that anon-uniform mixture is obtained. Needle-like morphologies can also giverise to filtration problems (See e.g., Mirmehrabi et al. J. Pharm. Sci.Vol. 93, No. 7, pp. 1692-1700, 2004). It is also desirable to increasethe dissolution rate of API-containing pharmaceutical compositions inwater, increase the bioavailability of orally-administered compositions,and provide a more rapid onset to therapeutic effect. It is alsodesirable to have a form of the API which, when administered to asubject, reaches a peak plasma level faster, has a longer lastingtherapeutic plasma concentration, and higher overall exposure whencompared to equivalent amounts of the API in its presently-known form.

Modafinil, an API used to treat subjects with narcolepsy, is practicallyinsoluble in water. Modafinil (CAS Registry Number: 68693-11-8) isrepresented by the structure (I):

Modafinil is a chiral molecule due to the chiral S═O group. Therefore,modafinil exists as two isomers, R-(−)-modafinil and S-(+)-modafinil. Itwould be advantageous to have new forms of modafinil that have improvedproperties, in particular, as oral formulations. Specifically, it isdesirable to identify improved forms of modafinil that exhibitsignificantly increased aqueous solubilities and both chemical and formstability. It is also desirable to increase the dissolution rate ofAPI-containing pharmaceutical compositions in water, increase thebioavailability of orally-administered compositions, and provide a morerapid onset to therapeutic effect. It is also desirable to have a formof the API which, when administered to a subject, reaches a peak plasmalevel faster and/or has a longer lasting plasma concentration and higheroverall exposure at high doses when compared to equivalent amounts ofthe API in its presently-known form.

SUMMARY OF THE INVENTION

It has now been found that co-crystals and solvates of modafinil can beobtained, many of which have different properties as compared to thefree form of the API.

Accordingly, in a first aspect, the present invention provides aco-crystal of modafinil, wherein the co-crystal former is an ether,thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester,phosphate ester, thiophosphate ester, ester, thioester, sulfate ester,carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide,primary amine, secondary amine, ammonia, tertiary amine, sp2 amine,thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro,S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole,O-heterocyclic ring, furan, epoxide, hydroxamic acid, imidazole, orpyridine.

The invention further provides a pharmaceutical composition comprising aco-crystal of modafinil. Typically, the pharmaceutical compositionfurther comprises one or more pharmaceutically-acceptable carriers,diluents or excipients. Pharmaceutical compositions according to theinvention are described in further detail below.

In a further aspect, the present invention provides a process for thepreparation of a co-crystal of modafinil, which comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising modafinil and the        co-crystal former.

In an embodiment, the co-crystal former has at least one functionalgroup selected from the group consisting of ether, thioether, alcohol,thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester,thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid,phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine,secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate,cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclicring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring,furan, epoxide, hydroxamic acid, imidazole, or pyridine.

Embodiments of the present invention including, but not limited to,co-crystals, polymorphs, and solvates can comprise racemic modafinil,enantiomerically pure modafinil (i.e., R-(−)-modafinil orS-(+)-modafinil), or enriched modafinil (e.g., between about 55 andabout 90 percent ee). Similarly, co-crystal formers and solventmolecules (e.g., in a solvate) can also exist as racemic,enantiomerically pure, or an enriched form in embodiments of the presentinvention.

In a further aspect, the present invention provides a process forincreasing the solubility of modafinil in water, simulated gastric fluid(SGF), or simulated intestinal fluid (SIF) for use in a pharmaceuticalcomposition or medicament, which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

In a further aspect, the present invention provides a process formodulating the dissolution of modafinil, whereby the aqueous dissolutionrate or the dissolution rate in simulated gastric fluid or in simulatedintestinal fluid, or in a solvent or plurality of solvents is increased,which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

In a further aspect, the present invention provides a process formodulating the bioavailability of modafinil, whereby the AUC isincreased, the time to T_(max) is reduced, the length of time theconcentration of modafinil is above ½ T_(max) is increased, or C_(max)is increased, which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

In a further aspect, the present invention provides a process formodulating the dose response of modafinil for use in a pharmaceuticalcomposition or medicament, which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

In a still further aspect the present invention provides a process forimproving the stability of modafinil (as compared to a reference formsuch as its free form), which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

In a still further aspect the present invention provides a process formodifying the morphology of modafinil, which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

In a still further aspect, the present invention therefore provides aprocess of screening for co-crystal compounds, which comprises:

-   -   (a) providing (i) modafinil and (ii) a co-crystal former        compatible with a functional group of modafinil such that the        co-crystal former and the modafinil can form a co-crystal; and    -   (b) screening for co-crystals of modafinil with a co-crystal        former by subjecting each combination of modafinil and        co-crystal former to a procedure comprising:        -   (i) grinding, heating, co-subliming, co-melting, or            contacting in solution the modafinil with the co-crystal            former under crystallization conditions, so as to form a            solid phase; and        -   (ii) isolating co-crystals comprising the modafinil and the            co-crystal former.

An alternative embodiment is drawn to a process of screening forco-crystal compounds, which comprises:

-   -   (a) providing (i) modafinil and (ii) a plurality of different        co-crystal formers compatible with a functional group of        modafinil such that each co-crystal former and the modafinil can        form a co-crystal; and    -   (b) screening for co-crystals of modafinil with co-crystal        formers by subjecting each combination of modafinil and        co-crystal former to a procedure comprising:        -   (i) grinding, heating, co-subliming, co-melting, or            contacting in solution the modafinil with the co-crystal            former under crystallization conditions, so as to form a            solid phase; and        -   (ii) isolating co-crystals comprising the modafinil and the            co-crystal former.

In a further aspect, the present invention provides a co-crystalcomposition comprising a co-crystal, wherein said co-crystal comprisesmodafinil and a co-crystal former. In further embodiments the co-crystalhas an improved property as compared to the free form (which includeshydrates and solvates). In further embodiments, the improved property isselected from the group consisting of: increased solubility, increaseddissolution, increased bioavailability, increased dose response, orother property described herein.

In another embodiment, the present invention provides a co-crystalcomprising modafinil and a co-crystal former selected from the groupconsisting of: malonic acid, glycolic acid, fumaric acid, tartaric acid,citric acid, succinic acid, gentisic acid, oxalic acid,1-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid,palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, andmaleic acid.

In further embodiments, the present invention provides the followingco-crystals: modafinil:malonic acid, modafinil:glycolic acid,modafinil:maleic acid, modafinil:L-tartaric acid, modafinil:citric acid,modafinil:succinic acid, modafinil:DL-tartaric acid, modafinil:fumaricacid (Form I), modafinil:fumaric acid (Form II), modafinil:gentisicacid, modafinil:oxalic acid, modafinil:1-hydroxy-2-naphthoic acid,R-(−)-modafinil:malonic acid, R-(−)-modafinil:succinic acid,R-(−)-modafinil:citric acid, R-(−)-modafinil:DL-tartaric acid,R-(−)-modafinil:1-hydroxy-2-naphthoic acid, R-(−)-modafinil:orotic acid,R-(−)-modafinil:glutaric acid, R-(−)-modafinil:L-tartaric acid,R-(−)-modafinil:palmitic acid, R-(−)-modafinil:L-proline,R-(−)-modafinil:salicylic acid, R-(−)-modafinil:lauric acid,R-(−)-modafinil:L-malic acid, and R-(−)-modafinil:gentisic acid.

In another embodiment, the present invention provides a novel polymorphor co-crystal of racemic modafinil (form VII).

In another embodiment, the present invention provides the followingmodafinil solvates: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol,nitromethane, acetone, o-xylene, benzene, ethanol, benzyl alcohol,isopropanol, acetonitrile, and toluene.

The processes according to the present invention may each comprise afurther step or steps in which the modafinil co-crystal produced therebyis incorporated into a pharmaceutical composition.

In another embodiment, a pharmaceutical composition comprises a modifiedrelease profile of one or more of racemic modafinil, R-(−)-modafinil,and S-(+)-modafinil. The modified release profile can comprise, forexample, two or more maxima of plasma concentration, such as adual-release profile.

The invention further provides a medicament comprising a co-crystal ofmodafinil and methods of making the same. Typically, the medicamentfurther comprises one or more pharmaceutically-acceptable carriers,diluents or excipients. Medicaments according to the invention aredescribed in further detail below.

The processes according to the present invention may each comprise afurther step or steps in which the modafinil co-crystal produced therebyis incorporated into a medicament.

In a still further aspect of the invention, a method is provided fortreating a subject, preferably a human subject, suffering from excessivedaytime sleepiness associated with narcolepsy, multiple sclerosisrelated fatigue, infertility, eating disorders, attention deficithyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleepapnea, or myopathies where modafinil is an effective activepharmaceutical for said disorder. The method comprises administering tothe subject a therapeutically-effective amount of a co-crystal or asolvate comprising modafinil, or a polymorph of modafinil.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1—PXRD diffractogram of a co-crystal comprising modafinil andmalonic acid.

FIG. 2—DSC thermogram of a co-crystal comprising modafinil and malonicacid.

FIG. 3—TGA thermogram of a co-crystal comprising modafinil and malonicacid.

FIGS. 4A and 4B—Raman spectrum of a co-crystal comprising modafinil andmalonic acid (FIG. 4A), and three Raman spectra of modafinil (bottomspectrum), malonic acid (middle spectrum), and a co-crystal comprisingmodafinil and malonic acid (top spectrum) (FIG. 4B).

FIGS. 5A and 5B—Infrared spectrum of a co-crystal comprising modafiniland malonic acid (FIG. 5A), and three Infrared spectra of modafinil (topspectrum), malonic acid (middle spectrum), and a co-crystal comprisingmodafinil and malonic acid (bottom spectrum) (FIG. 5B).

FIG. 6A—PXRD diffractogram of a co-crystal comprising modafinil andmalonic acid.

FIG. 6B—DSC thermogram of a co-crystal comprising modafinil and malonicacid (from grinding).

FIG. 7—Packing diagram for modafinil:malonic acid co-crystal.

FIGS. 8A and 8B—PXRD diffractograms of a co-crystal comprising modafiniland glycolic acid, background removed and as collected, respectively.

FIGS. 9A and 9B—PXRD diffractograms of a co-crystal comprising modafiniland maleic acid, background removed and as collected, respectively.

FIG. 10—PXRD diffractogram of a co-crystal comprising modafinil andL-tartaric acid.

FIG. 11A—PXRD diffractogram of a co-crystal comprising modafinil andcitric acid.

FIG. 11B—DSC thermogram of a co-crystal comprising modafinil and citricacid.

FIGS. 12A and 12B—PXRD diffractogram of a co-crystal comprisingmodafinil and succinic acid, background removed and as collected,respectively.

FIG. 13—DSC thermogram of a co-crystal comprising modafinil and succinicacid.

FIG. 14—Packing diagram of a co-crystal comprising modafinil andsuccinic acid.

FIG. 15—PXRD diffractogram of a co-crystal comprising modafinil andDL-tartaric acid.

FIG. 16—PXRD diffractogram of a co-crystal comprising modafinil andfumaric acid (Form I).

FIG. 17—Packing diagram of a co-crystal comprising modafinil and fumaricacid (Form I).

FIG. 18—PXRD diffractogram of a co-crystal comprising modafinil andfumaric acid (Form II).

FIG. 19—PXRD diffractogram of a co-crystal comprising modafinil andgentisic acid.

FIG. 20—PXRD diffractogram of a co-crystal comprising modafinil andoxalic acid.

FIG. 21—PXRD diffractogram of a co-crystal comprising modafinil and1-hydroxy-2-naphthoic acid.

FIG. 22—PXRD diffractogram of a co-crystal comprising R-(−)-modafiniland malonic acid.

FIG. 23—DSC thermogram of a co-crystal comprising R-(−)-modafinil andmalonic acid.

FIG. 24—PXRD diffractogram of a co-crystal comprising R-(−)-modafiniland succinic acid.

FIG. 25—DSC thermogram of a co-crystal comprising R-(−)-modafinil andsuccinic acid.

FIG. 26—PXRD diffractogram of a co-crystal comprising R-(−)-modafiniland citric acid.

FIG. 27—DSC thermogram of a co-crystal comprising R-(−)-modafinil andcitric acid.

FIG. 28—PXRD diffractogram of a co-crystal comprising R-(−)-modafiniland DL-tartaric acid.

FIG. 29—DSC thermogram of a co-crystal comprising R-(−)-modafinil andDL-tartaric acid.

FIG. 30—PXRD diffractogram of a co-crystal comprising R-(−)-modafiniland 1-hydroxy-2-naphthoic acid.

FIG. 31—DSC thermogram of a co-crystal comprising R-(−)-modafinil and1-hydroxy-2-naphthoic acid.

FIG. 32—PXRD diffractogram of a co-crystal comprising R-(−)-modafiniland 1-hydroxy-2-naphthoic acid obtained from a high throughputexperiment.

FIG. 33—PXRD diffractogram of a co-crystal comprising R-(−)-modafiniland orotic acid.

FIG. 34—DSC thermogram of a co-crystal comprising R-(−)-modafinil andorotic acid.

FIG. 35—PXRD diffractogram of a solvate comprising modafinil and aceticacid.

FIG. 36—TGA thermogram of a solvate comprising modafinil and aceticacid.

FIG. 37—DSC thermogram of a solvate comprising modafinil and aceticacid.

FIG. 38—Raman spectrum of a solvate comprising modafinil and aceticacid.

FIG. 39—PXRD diffractogram of a solvate comprising modafinil andtetrahydrofuran.

FIG. 40—PXRD diffractogram of a solvate comprising modafinil and1,4-dioxane.

FIG. 41—PXRD diffractogram of a solvate comprising modafinil andmethanol.

FIG. 42—TGA thermogram of a solvate comprising modafinil and methanol.

FIG. 43—DSC thermogram of a solvate comprising modafinil and methanol.

FIG. 44—PXRD diffractogram of a solvate comprising modafinil andnitromethane.

FIG. 45—PXRD diffractogram of a solvate comprising modafinil andacetone.

FIG. 46—PXRD diffractogram of a possible solvate comprising modafiniland acetone.

FIG. 47—PXRD diffractogram of a possible solvate comprising modafiniland 1,2-dichloroethane.

FIG. 48—PXRD diffractogram of a polymorph of modafinil (Form VI).

FIG. 49—Stability plot of modafinil:malonic acid co-crystal over a 26week period.

FIG. 50—Closer view of stability plot of modafinil:malonic acidco-crystal over a 26 week period.

FIG. 51—PXRD diffractogram comparison of modafinil:malonic acidco-crystal after several environmental conditions are endured.

FIG. 52—Dissolution profile of several formulations of modafinil freeform and modafinil:malonic acid.

FIG. 53—In Vitro dissolution profile of modafinil:malonic acidco-crystal in SGF and SIF.

FIG. 54—In Vitro dissolution profile of modafinil:malonic acidco-crystal in HCl.

FIG. 55—DVS plot of modafinil:malonic acid co-crystal.

FIG. 56—Pharmacokinetics of modafinil:malonic acid co-crystal in dogs.

FIG. 57—PXRD diffractogram of a co-crystal comprising R-(−)-modafiniland gentisic acid.

FIG. 58—Packing diagram of acetone channel solvate of modafinil.

FIG. 59—Additional packing diagram of acetone channel solvate ofmodafinil.

FIG. 60—PXRD diffractogram of o-xylene solvate.

FIG. 61—Raman spectrum of o-xylene solvate (middle spectrum).

FIG. 62—TGA thermogram of o-xylene solvate.

FIG. 63—DSC thermogram of o-xylene solvate.

FIG. 64—PXRD diffractogram of benzene solvate.

FIG. 65—Raman spectrum of benzene solvate (middle spectrum).

FIG. 66—TGA thermogram of benzene solvate.

FIG. 67—DSC thermogram of benzene solvate.

FIG. 68—PXRD diffractogram of toluene solvate.

FIG. 69—Raman spectrum of toluene solvate (middle spectrum).

FIG. 70—TGA thermogram of toluene solvate.

FIG. 71—DSC thermogram of toluene solvate.

FIG. 72—PXRD diffractogram of R-(−)-modafinil ethanol solvate.

FIG. 73—TGA thermogram of R-(−)-modafinil ethanol solvate.

FIG. 74—PXRD diffractogram of R-(−)-modafinil benzyl alcohol solvate.

FIG. 75—DSC thermogram of R-(−)-modafinil benzyl alcohol solvate.

FIG. 76—TGA thermogram of R-(−)-modafinil benzyl alcohol solvate.

FIG. 77—PXRD diffractogram of R-(−)-modafinil isopropanol solvate.

FIG. 78—PXRD diffractogram of R-(−)-modafinil acetonitrile solvate.

FIG. 79—PXRD diffractogram of R-(−)-modafinil:glutaric acid co-crystal.

FIG. 80—PXRD diffractogram of R-(−)-modafinil:citric acid co-crystal.

FIG. 81—PXRD diffractogram of R-(−)-modafinil:L-tartaric acidco-crystal.

FIGS. 82A and 82B—PXRD diffractograms of R-(−)-modafinil:oxalic acidco-crystal.

FIG. 83—PXRD diffractogram of R-(−)-modafinil:palmitic acid co-crystal.

FIG. 84—PXRD diffractogram of R-(−)-modafinil:L-proline co-crystal.

FIG. 85—PXRD diffractogram of R-(−)-modafinil:salicylic acid co-crystal.

FIG. 86—PXRD diffractogram of R-(−)-modafinil:lauric acid co-crystal.

FIG. 87—PXRD diffractogram of R-(−)-modafinil:L-malic acid co-crystal.

DETAILED DESCRIPTION OF THE INVENTION

The structure of modafinil includes a stereocenter and, therefore, canexist as a racemate, one of two pure isomers, or any ratio of the twoisomeric pairs. The chemical name of racemic modafinil is(±)-2-[(Diphenylmethyl)sulfinyl]acetamide. The isomeric pairs of racemicmodafinil are R-(−)-2-[(Diphenylmethyl)sulfinyl]acetamide orR-(−)-modafinil and S-(+)-2-[(Diphenylmethyl)sulfinyl]acetamide orS-(+)-modafinil.

As used herein and unless otherwise specified, the term“enantiomerically pure” includes a composition which is substantiallyenantiomerically pure and includes, for example, a composition withgreater than or equal to about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99percent enantiomeric excess. Enantiomeric excess is defined by percentenantiomer A-percent enantiomer B, or by the formula: eepercent=100*([R]−[S]/([R]+[S]), where R is moles of R-(−)-modafinil andS is moles of S-(+)-modafinil.

As used herein, the term “modafinil” includes the racemate, othermixtures of R- and S-isomers, and single enantiomers, but may bespecifically set forth as the racemate, R-isomer, S-isomer, or anymixture of both R- and S-isomers.

As used herein and unless otherwise specified, the term “racemicco-crystal” refers to a co-crystal which is comprised of an equimolarmixture of the enantiomers of modafinil, the co-crystal former, or both.For example, a co-crystal comprising modafinil and a non-stereoisomericco-crystal former is a “racemic co-crystal” only when there is presentan equimolar mixture of the modafinil enantiomers. Similarly, aco-crystal comprising modafinil and a stereoisomeric co-crystal formeris a “racemic co-crystal” only when there is present an equimolarmixture of the modafinil enantiomers and of the co-crystal formerenantiomers.

As used herein and unless otherwise specified, the term“enantiomerically pure co-crystal” refers to a co-crystal which iscomprised of modafinil and a stereoisomeric or non-stereoisomericco-crystal former where the enantiomeric excess of the stereoisomericspecies is greater than or equal to about 90 percent ee (enantiomericexcess).

The term “co-crystal” as used herein means a crystalline materialcomprised of two or more unique solids at room temperature (22 degreesC.), each containing distinctive physical characteristics, such asstructure, melting point, and heats of fusion, with the exception that,if specifically stated, the API may be a liquid at room temperature. Theco-crystals of the present invention comprise a co-crystal formerH-bonded to modafinil or a derivative thereof. The co-crystal former maybe H-bonded directly to modafinil or may be H-bonded to an additionalmolecule which is bound to modafinil. The additional molecule may beH-bonded to modafinil or bound ionically to modafinil. The additionalmolecule could also be a different API. Solvates of modafinil compoundsthat do not further comprise a co-crystal former are not co-crystalsaccording to the present invention. The co-crystals may however, includeone or more solvate molecules in the crystalline lattice. That is, asolvate of co-crystal, or a co-crystal further comprising a solvent orcompound that is a liquid at room temperature, is a co-crystal accordingto the present invention, but crystalline material comprised of onlymodafinil and one or more liquids (at room temperature) are notco-crystals for purposes of the present invention. Other modes ofmolecular recognition may also be present including, pi-stacking,guest-host complexation and van der Waals interactions. Of theinteractions listed above, hydrogen-bonding is the dominant interactionin the formation of the co-crystal, (and a required interactionaccording to the present invention) whereby a non-covalent bond isformed between a hydrogen bond donor of one of the moieties and ahydrogen bond acceptor of the other. Hydrogen bonding can result inseveral different intermolecular configurations. For example, hydrogenbonds can result in the formation of dimers, linear chains, or cyclicstructures. These configurations can further include extended(two-dimensional) hydrogen bond networks and isolated triads. Analternative embodiment provides for a co-crystal wherein the co-crystalformer is a second API. In another embodiment, the co-crystal former isnot an API.

For purposes of the present invention, the chemical and physicalproperties of modafinil in the form of a co-crystal may be compared to areference compound that is modafinil in a different form. The referencecompound may be specified as a free form, or more specifically, ananhydrate or hydrate of a free form, or more specifically, for example,a hemihydrate, monohydrate, dihydrate, trihydrate, quadrahydrate,pentahydrate; or a solvate of a free form. For example, the referencecompound for modafinil in free form co-crystallized with a co-crystalformer can be modafinil in free form. The reference compound may also bespecified as crystalline or amorphous. The reference compound may alsobe specified as the most stable polymorph known of the specified form ofthe reference compound.

The ratio of modafinil to co-crystal former may be stoichiometric ornon-stoichiometric according to the present invention. Non-limitingexamples such as, 1:1, 1:1.5, 1.5:1, 1:2, and 2:1 ratios ofmodafinil:co-crystal former are acceptable. In addition, co-crystalswith vacancies within the crystalline lattice are included in thepresent invention. For example, a co-crystal with less than or about0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, or 20 percent vacancies within the crystalline lattice areincluded in the present invention. The vacancies can be due to missingmodafinil molecules or missing co-crystal former molecules from thecrystalline lattice, or both.

It has surprisingly been found that when modafinil and a selectedco-crystal former are allowed to form co-crystals, the resultingco-crystals often give rise to improved properties of modafinil, ascompared to modafinil in the free form, particularly with respect to:solubility, dissolution, bioavailability, stability, C_(max), T_(max),processability (including compressibility), longer lasting therapeuticplasma concentration, etc. For example, a co-crystal form of modafinilis particularly advantageous due to the low solubility of modafinil inwater. Additionally, the co-crystal properties conferred upon modafinilare also useful because the bioavailability of modafinil can be improvedand the plasma concentration and/or serum concentration of modafinil canbe improved. This is particularly advantageous for orally-administrableformulations. Moreover, the dose response of modafinil can be improved,for example by increasing the maximum attainable response and/orincreasing the potency of modafinil by increasing the biologicalactivity per dosing equivalent.

Accordingly, in a first aspect, the present invention provides apharmaceutical composition (or medicament) comprising a co-crystal ofmodafinil and a co-crystal former, such that the modafinil and theco-crystal former are capable of co-crystallizing from a solution phaseunder crystallization conditions or from the solid-state, for example,through grinding or heating. In another aspect, the co-crystal formerwhich has at least one functional group selected from the groupconsisting of ether, thioether, alcohol, thiol, aldehyde, ketone,thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester,thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinicacid, sulfonic acid, amide, primary amine, secondary amine, ammonia,tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile,diazo, organohalide, nitro, S-heterocyclic ring, thiophene,N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide,hydroxamic acid, imidazole, and pyridine, or a functional group in aTable herein, such that the modafinil and co-crystal former are capableof co-crystallizing from a solution phase under crystallizationconditions.

In another embodiment, the use of an excess (more than 1 molarequivalent for a 1:1 co-crystal) of a co-crystal former can be used todrive the formation of stoichiometric co-crystals. For example,co-crystals with stoichiometries of 1:1, 2:1, or 1:2 can be produced byadding co-crystal former in an amount that is 2, 3, 4, 5, 6, 7, 8, 9,10, 15, 20, 25, 50, 75, 100 times or more than the stoichiometric amountfor a given co-crystal. Such an excessive use of a co-crystal former toform a co-crystal can be employed in solution or when grinding modafiniland a co-crystal former to cause co-crystal formation.

In another embodiment of the present invention, a modafinil co-crystalfurther comprises a co-crystal former which is hydrogen bonded via apreferred interaction between two or more functional groups. Forexample, modafinil and malonic acid co-crystallize through theinteraction of a carboxylic acid functional group of the co-crystalformer with sulfoxide and amide functional groups of modafinil.

In another embodiment of the present invention, the co-crystal comprisesmodafinil wherein the modafinil forms a dimeric primary amide structurevia hydrogen bonds with an R² ₂ (8) motif. See e.g., J. Bernstein,Polymorphism in Molecular Crystals, Oxford University Press, 2002, pp.55-59, or M. C. Etter, Acct. Chem. Res., 1990, 23, 120, or M. C. Etter,J. Phys. Chem., 1991, 95, 4601. In such a structure, the NH₂ moiety canalso participate in a hydrogen bond with a donor or an acceptor moietyfrom, for example, a co-crystal former or an additional (third)molecule, and the C═O moiety can participate in a hydrogen bond with adonor moiety from the co-crystal former or the additional molecule. In afurther embodiment, the dimeric primary amide structure (formed by twomodafinil molecules) further comprises one, two, three, or four hydrogenbond donors (from one, two, three, or four co-crystal formers). In afurther embodiment, the dimeric primary amide structure furthercomprises one or two hydrogen bond acceptors (from one or two co-crystalformers). In a further embodiment, the dimeric primary amide structurefurther comprises a combination of hydrogen bond donors and acceptors.For example, the dimeric primary amide structure can further compriseone hydrogen bond donor and one hydrogen bond acceptor, one hydrogenbond donor and two hydrogen bond acceptors, two hydrogen bond donors andone hydrogen bond acceptor, two hydrogen bond donors and two hydrogenbond acceptors, or three hydrogen bond donors and one hydrogen bondacceptor.

The co-crystals of the present invention are formed where modafinil andthe co-crystal former are bonded together through hydrogen bonds. Othernon-covalent interactions, including pi-stacking and van der Waalsinteractions, may also be present.

In one embodiment, the co-crystal former is selected from the co-crystalformers of Table I and Table II. In other embodiments, the co-crystalformer of Table I is specified as a Class 1, Class 2, or Class 3co-crystal former (see column labeled “class” Table I). Table I listsmultiple pK_(a) values for co-crystal formers having multiplefunctionalities. It is readily apparent to one skilled in the art theparticular functional group corresponding to a particular pK_(a) value.

In another embodiment the particular functional group of a co-crystalformer interacting with modafinil is specified (see for example Table I,columns labeled “Functionality” and “Molecular Structure” and the columnof Table II labeled “Co-Crystal Former Functional Group”).

In another embodiment, the co-crystal comprises more than one co-crystalformer. For example, two, three, four, five, or more co-crystal formerscan be incorporated in a co-crystal with modafinil. Co-crystals whichcomprise two or more co-crystal formers and an API are bound togethervia hydrogen bonds. In one embodiment, incorporated co-crystal formersare hydrogen bonded to modafinil molecules. In another embodiment,co-crystal formers are hydrogen bonded to either the modafinil moleculesor the incorporated co-crystal formers.

In each process according to the invention, there is a need to contactmodafinil with the co-crystal former. This may involve grinding the twosolids together or melting one or both components and allowing them torecrystallize. This may also involve either solubilizing modafinil andadding the co-crystal former, or solubilizing the co-crystal former andadding modafinil. Crystallization conditions are applied to modafiniland the co-crystal former. This may entail altering a property of thesolution, such as pH or temperature and may require concentration of thesolute, usually by removal of the solvent, typically by drying thesolution. Solvent removal results in the concentration of both modafiniland the co-crystal former increasing over time so as to facilitatecrystallization. For example, evaporation, cooling, or the addition ofan antisolvent may be used to crystallize co-crystals. In anotherembodiment, a slurry comprising modafinil and a co-crystal former isused to form co-crystals. Once the solid phase comprising any crystalsis formed, this may be tested as described herein.

The co-crystals obtained as a result of such process steps may bereadily incorporated into a pharmaceutical composition (or medicament)by conventional means. Pharmaceutical compositions and medicaments ingeneral are discussed in further detail below and may further comprise apharmaceutically-acceptable diluent, excipient or carrier.

In a further aspect, the present invention provides a process for thepreparation of a co-crystal of modafinil, which comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising modafinil and the        co-crystal former.

In an embodiment, the co-crystal former has at least one functionalgroup selected from the group consisting of ether, thioether, alcohol,thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester,thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid,phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine,secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate,cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclicring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring,furan, epoxide, hydroxamic acid, imidazole, or pyridine.

In a further aspect, the present invention provides a process for theproduction of a pharmaceutical composition or medicament, which processcomprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions;    -   (d) isolating co-crystals formed thereby; and    -   (e) incorporating the co-crystals into a pharmaceutical        composition or medicament.

In another embodiment, a process for the formation of co-crystalsincludes a meta-stable form of modafinil, the co-crystal former, orboth. A meta-stable form can be for example, but not limited to, apolymorph, solvate, or hydrate of modafinil or the co-crystal former.While not bound by theory, the incorporation of a meta-stable form mayfacilitate co-crystal formation via increasing the thermodynamic drivingforce.

Assaying the solid phase for the presence of co-crystals of modafiniland the co-crystal former may be carried out by conventional methodsknown in the art. For example, it is convenient and routine to usepowder X-ray diffraction techniques to assess the presence ofco-crystals. This may be affected by comparing the diffractograms ofmodafinil, the crystal former and putative co-crystals in order toestablish whether or not true co-crystals had been formed. Othertechniques, used in an analogous fashion, include differential scanningcalorimetry (DSC), thermogravimetric analysis (TGA), infraredspectroscopy (IR), and Raman spectroscopy. Single crystal X-raydiffraction is especially useful in identifying co-crystal structures.

In a further aspect, the present invention therefore provides a processof screening for co-crystal compounds, which comprises:

-   -   (a) providing (i) modafinil and (ii) a co-crystal former        compatible with a functional group of modafinil such that the        co-crystal former and the modafinil can form a co-crystal; and    -   (b) screening for co-crystals of the modafinil with the        co-crystal former by subjecting each combination of modafinil        and co-crystal former to a procedure comprising:        -   (i) grinding, heating, co-subliming, co-melting, or            contacting in solution the modafinil with the co-crystal            former under crystallization conditions so as to form a            solid phase; and        -   (ii) isolating co-crystals comprising the modafinil and the            co-crystal former.

An alternative embodiment is drawn to a process of screening forco-crystal compounds, which comprises:

-   -   (a) providing (i) modafinil and (it) a plurality of different        co-crystal formers compatible with a functional group of        modafinil such that the co-crystal former and the modafinil can        form a co-crystal; and    -   (b) screening for co-crystals of the modafinil with the        co-crystal formers by subjecting each combination of the        modafinil and the co-crystal formers to a procedure comprising:        -   (i) grinding, heating, co-subliming, co-melting, or            contacting in solution the modafinil with each co-crystal            former under crystallization conditions so as to form a            solid phase; and        -   (ii) isolating co-crystals comprising the modafinil and the            co-crystal former.

The present invention includes several co-crystals comprising modafiniland a carboxylic acid co-crystal former. Some examples include modafinilco-crystals comprising malonic acid, tartaric acid (L- and DL-),succinic acid, citric acid, fumaric acid, gentisic acid, oxalic acid,and 1-hydroxy-2-naphthoic acid. These examples represent mono-, di- andtri-carboxylic acid co-crystal formers. Other acids, includingcarboxylic acids, may be used as co-crystal formers with modafinilincluding, but not limited to, palmitic acid, orotic acid, and adipicacid etc. These co-crystal formers may comprise one, two, three, or morecarboxylic acid functional groups. Co-crystal formers can also includenon-carboxylic acid molecules such as, but not limited to, urea,saccharin, and caffeine.

In another embodiment, a co-crystal comprises modafinil and a carboxylicacid as a co-crystal former. In another embodiment, the carboxylic acidco-crystal former has one, two, three, or more carboxylic acidfunctional groups.

Several co-crystals may exhibit one or more particular interactionsbetween modafinil and a carboxylic acid co-crystal former. For example,a carboxylic acid functional group can interact with the primary amideand/or the S═O functional group of modafinil via a hydrogen bond. Inanother embodiment, a carboxylic acid functional group from theco-crystal former interacts with the primary amide functional group orthe S═O functional group of modafinil via a hydrogen bond. In anotherembodiment, a carboxylic acid functional group from the co-crystalformer interacts with the periphery of the amide dimer of modafinil viaa hydrogen bond. In another embodiment, a carboxylic acid functionalgroup from the co-crystal former interacts with the amide dimer and theS═O functional group of modafinil via a hydrogen bond. In anotherembodiment, a carboxylic acid functional group from the co-crystalformer interacts with two amide dimers of modafinil via a hydrogen bond.

Modafinil and some co-crystal formers of the present invention have oneor more chiral centers and may exist in a variety of stereoisomericconfigurations. As a consequence of these chiral centers, modafinil andseveral co-crystal formers of the present invention occur as racemates,mixtures of enantiomers and as individual enantiomers, as well asdiastereomers and mixtures of diastereomers. All such racemates,enantiomers, and diastereomers are within the scope of the presentinvention including, for example, cis- and trans-isomers, R- andS-enantiomers, and (D)- and (L)-isomers. Co-crystals of the presentinvention can include isomeric forms of either modafinil or theco-crystal former or both. Isomeric forms of modafinil and co-crystalformers include, but are not limited to, stereoisomers such asenantiomers and diastereomers. In one embodiment, a co-crystal cancomprise racemic modafinil and/or a co-crystal former. In anotherembodiment, a co-crystal can comprise enantiomerically pure R- orS-modafinil and/or a co-crystal former. In another embodiment, aco-crystal of the present invention can comprise modafinil or aco-crystal former with an enantiomeric excess of about 1 percent, 2percent, 3 percent, 4 percent, 5 percent, 10 percent, 15 percent, 20percent, 25 percent, 30 percent, 35 percent, 40 percent, 45 percent, 50percent, 55 percent, 60 percent, 65 percent, 70 percent, 75 percent, 80percent, 85 percent, 90 percent, 95 percent, 96 percent, 97 percent, 98percent, 99 percent, greater than 99 percent, or any intermediate value.Several non-limiting examples of stereoisomeric co-crystal formersinclude tartaric acid and malic acid. In another embodiment, a polymorphor a solvate of the present invention can comprise modafinil with anenantiomeric excess of about 1 percent, 2 percent, 3 percent, 4 percent,5 percent, 10 percent, 15 percent, 20 percent, 25 percent, 30 percent,35 percent, 40 percent, 45 percent, 50 percent, 55 percent, 60 percent,65 percent, 70 percent, 75 percent, 80 percent, 85 percent, 90 percent,95 percent, 96 percent, 97 percent, 98 percent, 99 percent, greater than99 percent, or any intermediate value.

“Enriched” modafinil, according to the present invention, comprises boththe R-(−)- and S-(+)-isomers of modafinil in amounts greater than orequal to about 5, 6, 7, 8, 9, or 10 percent by weight and less than orequal to about 90, 91, 92, 93, 94, or 95 percent by weight. For example,a composition comprising 67 percent by weight R-(−)-modafinil and 33percent by weight S-(+)-modafinil is an enriched modafinil composition.In such an example, the composition is neither racemic norenantiomerically pure. The term “enriched R-(−)-modafinil” may be usedto describe a composition of modafinil with greater than 50 percentR-(−)-modafinil and less than 50 percent S-(+)-modafinil. Likewise, theterm “enriched S-(+)-modafinil” may be used to describe a composition ofmodafinil with greater than 50 percent S-(+)-modafinil and less than 50percent R-(−)-modafinil.

The terms “R-(−)-modafinil” and “S-(+)-modafinil” can be used todescribe enriched modafinil, enantiomerically pure modafinil, orsubstantially enantiomerically pure modafinil, but may also specificallyexclude enriched modafinil, enantiomerically pure modafinil, and/orsubstantially enantiomerically pure modafinil.

Co-crystals, solvates, and polymorphs comprising enantiomerically pureand/or enantiomerically enriched components (e.g., modafinil orco-crystal former) can give rise to chemical and/or physical propertieswhich are modulated with respect to those of the correspondingco-crystal comprising a racemic component. For example, themodafinil:malonic acid co-crystal from Example 1 comprises racemicmodafinil. Enantiomerically pure R-(−)-modafinil:malonic acid isincluded in the scope of the invention. Likewise, enantiomerically pureS-(+)-modafinil:malonic acid is included in the scope of the invention.A co-crystal comprising an enantiomerically pure component can give riseto a modulation of, for example, activity, bioavailability, orsolubility, with respect to the corresponding co-crystal comprising aracemic component. As an example, the co-crystal R-(−)-modafinil:malonicacid can have modulated properties as compared to the racemicmodafinil:malonic acid co-crystal.

Polymorphs and solvates of modafinil can also be prepared with racemicmodafinil, enantiomerically pure modafinil, or with any mixture ofR-(−)- and S-(+)-modafinil according to the present invention.

In another embodiment, the present invention includes a pharmaceuticalcomposition or medicament comprising a co-crystal with enantiomericallypure modafinil and/or co-crystal former wherein the bioavailability ismodulated with respect to the racemic co-crystal. In another embodiment,the present invention includes a pharmaceutical composition ormedicament comprising a co-crystal with enantiomerically pure modafiniland/or co-crystal former wherein the activity is modulated with respectto the racemic co-crystal. In another embodiment, the present inventionincludes a pharmaceutical composition or medicament comprising aco-crystal with enantiomerically pure modafinil and/or co-crystal formerwherein the solubility is modulated with respect to the racemicco-crystal.

In another embodiment, a pharmaceutical composition or medicament can beformulated to contain modafinil in co-crystal form as micronized ornano-sized particles. More specifically, another embodiment couples theprocessing of pure modafinil to a co-crystal form with the process ofmaking a controlled particle size for manipulation into a pharmaceuticaldosage form. This embodiment combines two processing steps into a singlestep via techniques such as, but not limited to, grinding, alloying, orsintering (i.e., heating a powder mix). The coupling of these processesovercomes a serious limitation of having to isolate and store the bulkdrug that is required for a formulation, which in some cases can bedifficult to isolate (e.g., amorphous, chemically or physicallyunstable).

Solubility Modulation

In a further aspect, the present invention provides a process forincreasing the solubility of modafinil in water, simulated gastric fluid(SGF), or simulated intestinal fluid (SIF) for use in a pharmaceuticalcomposition or medicament, which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

In one embodiment, the solubility of modafinil is modulated such thatthe aqueous solubility (mg/mL) is increased by at least 1.1, 1.2, 1.3,1.5, 2.0, 5.0, 10.0, 20.0, 25.0, 50.0, 75.0, or 100.0 times or more thanthe free form. Solubility of modafinil may be measured by anyconventional means such as chromatography (e.g., HPLC) or spectroscopicdetermination of the amount of modafinil in a saturated solution, suchas UV-spectroscopy, IR-spectroscopy, Raman spectroscopy, quantitativemass spectroscopy, or gas chromatography.

In another embodiment, the compositions or medicaments includingco-crystals, solvates, and polymorphs of the present invention can becompared with free form modafinil as found in PROVIGIL® (Cephalon,Inc.). (See U.S. Reissued Pat. No. RE37,516) For example, thebioavailability of a composition or medicament of the present inventioncan be compared with that of PROVIGIL. As embodiments of the presentinvention, solubility can be increased 2, 3, 4, 5, 7, 10, 15, 20, 25,50, 75, or 100 times by making a co-crystal of the reference form (e.g.,crystalline or amorphous free form, hydrate or solvate). Further aqueoussolubility can be measured in simulated gastric fluid (SGF) or simulatedintestinal fluid (SIF) rather than water. SGF (non-diluted) of thepresent invention is made by combining 1 g/L Triton X-100 and 2 g/L NaClin water and adjusting the pH with 20 mM HCl to obtain a solution with afinal pH=1.7 SIF is 0.68% monobasic potassium phosphate, 1% pancreatin,and sodium hydroxide where the pH of the final solution is 7.5. The pHof the solvent used may also be specified as 1, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3,3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5,or 12, or any pH in between successive values.

Examples of embodiments includes: co-crystal compositions with anaqueous solubility, at 37 degrees C. and a pH of 7.0, that is increasedat least 5 fold over the reference form, co-crystal compositions with asolubility in SGF that is increased at least 5 fold over the referenceform, co-crystal compositions with a solubility in SIF that is increasedat least 5 fold over the reference form.

Dissolution Modulation

In another aspect of the present invention, the dissolution profile ofmodafinil is modulated whereby the aqueous dissolution rate or thedissolution rate in simulated gastric fluid or in simulated intestinalfluid, or in a solvent or plurality of solvents is increased.Dissolution rate is the rate at which API solids dissolve in adissolution medium. For APIs whose absorption rates are faster than thedissolution rates (e.g., steroids), the rate-limiting step in theabsorption process is often the dissolution rate. Because of a limitedresidence time at the absorption site, APIs that are not dissolvedbefore they are removed from intestinal absorption site are considereduseless. Therefore, the rate of dissolution has a major impact on theperformance of APIs that are poorly soluble. Because of this factor, thedissolution rate of APIs in solid dosage forms is an important, routine,quality control parameter used in the API manufacturing process. Thefollowing equation is an approximation,Dissolution rate=KS(C _(s) −C)where K is dissolution rate constant, S is the surface area, C_(s) isthe apparent solubility, and C is the concentration of API in thedissolution medium.For rapid API absorption, C_(s)−C is approximately equal to C_(s)

The dissolution rate of modafinil may be measured by conventional meansknown in the art.

The increase in the dissolution rate of a co-crystal, as compared to thereference form (e.g., free form), may be specified, such as by 10, 20,30, 40, 50, 60, 70, 80, 90, or 100%, or by 2, 3, 4, 5, 6, 7, 8, 9, 10,15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400,500, 1000, 10,000, or 100,000 fold greater than the reference form(e.g., free form) in the same solution. Conditions under which thedissolution rate is measured are the same as discussed above. Theincrease in dissolution may be further specified by the time thecomposition remains supersaturated before reaching equilibriumsolubility.

In a further aspect, the present invention provides a process formodulating the dissolution of modafinil, whereby the aqueous dissolutionrate or the dissolution rate in simulated gastric fluid or in simulatedintestinal fluid, or in a solvent or plurality of solvents is increased,which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

Examples of above embodiments include: co-crystal compositions with adissolution rate in aqueous solution, at 37 degrees C. and a pH of 7.0,that is increased at least 5 fold over the reference form, co-crystalcompositions with a dissolution rate in SGF that is increased at least 5fold over the reference form, co-crystal compositions with a dissolutionrate in SIF that is increased at least 5 fold over the reference form.

Bioavailability Modulation

The methods of the present invention are used to make a pharmaceuticalmodafinil formulation with greater solubility, dissolution, andbioavailability. Bioavailability can be improved via an increase in AUC,reduced time to T_(max), (the time to reach peak blood serum levels), orincreased C_(max). The present invention can result in higher plasmaconcentrations of modafinil when compared to the free form (referenceform).

AUC is the area under the plot of plasma concentration of API (notlogarithm of the concentration) against time after API administration.The area is conveniently determined by the “trapezoidal rule”: The datapoints are connected by straight line segments, perpendiculars areerected from the abscissa to each data point, and the sum of the areasof the triangles and trapezoids so constructed is computed. When thelast measured concentration (C_(n), at time t_(n)) is not zero, the AUCfrom t_(n) to infinite time is estimated by C_(n)/k_(ci).

The AUC is of particular use in estimating bioavailability of APIs, andin estimating total clearance of APIs (Cl_(T)). Following singleintravenous doses, AUC D/Cl_(T), for single compartment systems obeyingfirst-order elimination kinetics, where D is the dose; alternatively,AUC=C₀/k_(el), where k_(el) is the API elimination rate constant. Withroutes other than the intravenous, AUC=F·D/Cl_(T), where F is theabsolute bioavailability of the API.

In a further aspect, the present invention provides a process formodulating the bioavailability of modafinil, whereby the AUC isincreased, the time to T_(max) is reduced, the length of time theconcentration of modafinil is above ½ T_(max) is increased, or C_(max)is increased, which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

Examples of the above embodiments include: co-crystal compositions witha time to T_(max) that is increased by at least 5% as compared to thereference form, co-crystal compositions with a time to T_(max) that isincreased by at least 10% over the reference form, co-crystalcompositions with a time to T_(max) that is increased by at least 15%over the reference form, co-crystal compositions with a time to T_(max)that is increased by at least 20% over the reference form, co-crystalcompositions with a T_(max) that is increased by at least 25% over thereference form, co-crystal compositions with a T_(max) that is increasedby at least 30% over the reference form, co-crystal compositions with aT_(max) that is increased by at least 35% over the reference form,co-crystal compositions with a T_(max) that is increased by at least 40%over the reference form, co-crystal compositions with an AUC that isincreased by at least 5% over the reference form, co-crystalcompositions with an AUC that is increased by at least 10% over thereference form, co-crystal compositions with an AUC that is increased byat least 15% over the reference form, co-crystal compositions with anAUC that is increased by at least 20% over the reference form,co-crystal compositions with an AUC that is increased by at least 25%over the reference form, co-crystal compositions with an AUC that isincreased by at least 30% over the reference form, co-crystalcompositions with an AUC that is increased by at least 35% over thereference form, co-crystal compositions with an AUC that is increased byat least 40% over the reference form. Other examples include wherein thereference form is crystalline, wherein the reference form is amorphous,or wherein the reference form is an anhydrous crystal form of modafinil.

Dose Response Modulation

In a further aspect, the present invention provides a process formodulating the dose response of modafinil for use in a pharmaceuticalcomposition or medicament, which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

Dose response is the quantitative relationship between the magnitude ofresponse and the dose inducing the response and may be measured byconventional means known in the art. The curve relating effect (as thedependent variable) to dose (as the independent variable) for anAPI-cell system is the “dose-response curve”. Typically, thedose-response curve is the measured response to an API plotted againstthe dose of the API (mg/kg) given. The dose response curve can also be acurve of AUC against the dose of the API given.

In an embodiment of the present invention, a co-crystal of the presentinvention has an increased dose response curve or a more linear doseresponse curve than the corresponding reference compound.

Increased Stability

In a still further aspect the present invention provides a process forimproving the stability of modafinil (as compared to a reference formsuch as its free form), which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting or contacting in        solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

In a preferred embodiment, the compositions of the present invention,including modafinil co-crystals, solvates, and formulations comprisingmodafinil, are suitably stable for pharmaceutical use. Preferably,modafinil or formulations thereof, of the present invention, are stablesuch that when stored at 30 degrees C. for 2 years, less than 0.2% ofany one degradant is formed. The term degradant refers herein toproduct(s) of a single type of chemical reaction. For example, if ahydrolysis event occurs that cleaves a molecule into two products, forthe purpose of the present invention, it would be considered a singledegradant. More preferably, when stored at 40 degrees C. for 2 years,less than 0.2% of any one degradant is formed. Alternatively, whenstored at 30 degrees C. for 3 months, less than 0.2% or 0.15%, or 0.1%of any one degradant is formed, or when stored at 40 degrees C. for 3months, less than 0.2% or 0.15%, or 0.1% of any one degradant is formed.Further alternatively, when stored at 60 degrees C. for 4 weeks, lessthan 0.2% or 0.15%, or 0.1% of any one degradant is formed. The relativehumidity (RH) may be specified as ambient RH, 75% RH, or as any singleinteger between 1 to 99% RH. In another embodiment, a single dose of thepresent invention comprises less than 0.5%, 0.2%, or 0.1% degradantsupon administration to a subject.

Morphology Modulation

In a still further aspect the present invention provides a process formodifying the morphology of modafinil, which process comprises:

-   -   (a) providing modafinil;    -   (b) providing a co-crystal former compatible with a functional        group of modafinil such that the co-crystal former and the        modafinil can form a co-crystal;    -   (c) grinding, heating, co-subliming, co-melting, or contacting        in solution the modafinil with the co-crystal former under        crystallization conditions, so as to form a solid phase; and    -   (d) isolating co-crystals comprising the modafinil and the        co-crystal former.

In an embodiment the co-crystal comprises or consists of modafinil and aco-crystal former wherein the interaction between the two, e.g.,H-bonding, occurs between the amino group of modafinil and a co-crystalformer with a corresponding interacting group of Table III. In a furtherembodiment, the co-crystal comprises modafinil and a co-crystal formerof Table I or II. In an aspect of the invention, only co-crystals havingan H-bond acceptor on the first molecule and an H-bond donor on thesecond molecule, where the first and second molecules are eitherco-crystal former and modafinil respectively, or modafinil andco-crystal former respectively, are included in the present invention.

A co-crystal can comprise more than two chemical entities within itsco-crystalline structure. For example, a co-crystal can further comprisea solvent molecule, a water molecule, a salt, etc. In addition, aco-crystal can comprise an API and two or more co-crystal formers, aco-crystal former and two or more APIs, two or more APIs, or two or moreco-crystal formers.

As defined herein, a ternary co-crystal is a co-crystal which comprisesthree distinct chemical entities in a stoichiometric ratio, where eachis a solid at room temperature (with the exception that the API may be aliquid at room temperature). Specifically, a ternary co-crystalcomprises three distinct chemical entities such as API:co-crystalformer(1):co-crystal former(2), where the ratio of components can be,for example, but not limited to, 1:1:1, 2:1:1, 2:1:2, 2:1:0.5, 2:2:1,etc. Ternary co-crystals can also comprise other combinations ofcomponents such as, but not limited to, API(1):API(2):co-crystal former,API(1):API(2):API(3), and co-crystal former(1):co-crystalformer(2):co-crystal former(3).

In another embodiment, the present invention provides a co-crystalcomprising modafinil and a co-crystal former selected from the groupconsisting of: malonic acid, glycolic acid, fumaric acid, tartaric acid,citric acid, succinic acid, gentisic acid, oxalic acid,1-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid,palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, andmaleic acid.

In further embodiments, the present invention provides the followingco-crystals: modafinil:malonic acid, modafinil:glycolic acid,modafinil:maleic acid, modafinil:L-tartaric acid, modafinil:citric acid,modafinil:succinic acid, modafinil:DL-tartaric acid, modafinil:fumaricacid (Form I), modafinil:fumaric acid (Form II), modafinil:gentisicacid, modafinil:oxalic acid, modafinil:1-hydroxy-2-naphthoic acid,R-(−)-modafinil:malonic acid, R-(−)-modafinil:succinic acid,R-(−)-modafinil:citric acid, R-(−)-modafinil:DL-tartaric acid,R-(−)-modafinil:1-hydroxy-2-naphthoic acid, R-(−)-modafinil:orotic acid,R-(−)-modafinil:glutaric acid, R-(−)-modafinil:L-tartaric acid,R-(−)-modafinil:palmitic acid, R-(−)-modafinil:L-proline,R-(−)-modafinil:salicylic acid, R-(−)-modafinil:lauric acid,R-(−)-modafinil:L-malic acid, and R-(−)-modafinil:gentisic acid.

In another embodiment, the present invention provides a novel polymorphor co-crystal of racemic modafinil (form VII).

In another embodiment, the present invention provides the followingmodafinil solvates: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol,nitromethane, acetone, o-xylene, benzene, and toluene.

Pharmaceutically acceptable co-crystals can be administered bycontrolled- or delayed-release means. Controlled-release pharmaceuticalproducts have a common goal of improving drug therapy over that achievedby their non-controlled release counterparts. Ideally, the use of anoptimally designed controlled-release preparation in medical treatmentis characterized by a minimum of drug substance being employed to cureor control the condition in a minimum amount of time. Advantages ofcontrolled-release formulations include: 1) extended activity of thedrug; 2) reduced dosage frequency; 3) increased patient compliance; 4)usage of less total drug; 5) reduction in local or systemic sideeffects; 6) minimization of drug accumulation; 7) reduction in bloodlevel fluctuations; 8) improvement in efficacy of treatment; 9)reduction of potentiation or loss of drug activity; and 10) improvementin speed of control of diseases or conditions. (Kim, Cherng-ju,Controlled Release Dosage Form Design, 2 Technomic Publishing,Lancaster, Pa.: 2000).

Conventional dosage forms generally provide rapid or immediate drugrelease from the formulation. Depending on the pharmacology andpharmacokinetics of the drug, use of conventional dosage forms can leadto wide fluctuations in the concentrations of the drug in a patient'sblood and other tissues. These fluctuations can impact a number ofparameters, such as dose frequency, onset of action, duration ofefficacy, maintenance of therapeutic blood levels, toxicity, sideeffects, and the like. Advantageously, controlled-release formulationscan be used to control a drug's onset of action, duration of action,plasma levels within the therapeutic window, and peak blood levels. Inparticular, controlled- or extended-release dosage forms or formulationscan be used to ensure that the maximum effectiveness of a drug isachieved while minimizing potential adverse effects and safety concerns,which can occur both from under dosing a drug (i.e., going below theminimum therapeutic levels) as well as exceeding the toxicity level forthe drug.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release other amountsof drug to maintain this level of therapeutic or prophylactic effectover an extended period of time. In order to maintain this constantlevel of drug in the body, the drug must be released from the dosageform at a rate that will replace the amount of drug being metabolizedand excreted from the body. Controlled-release of an active ingredientcan be stimulated by various conditions including, but not limited to,pH, ionic strength, osmotic pressure, temperature, enzymes, water, andother physiological conditions or compounds.

A variety of known controlled- or extended-release dosage forms,formulations, and devices can be adapted for use with the co-crystalsand compositions of the invention. Examples include, but are not limitedto, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 B1; each ofwhich is incorporated herein by reference. These dosage forms can beused to provide slow or controlled-release of one or more activeingredients using, for example, hydroxypropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems (such asOROS® (Alza Corporation, Mountain View, Calif. USA)), multilayercoatings, microparticles, liposomes, or microspheres or a combinationthereof to provide the desired release profile in varying proportions.Additionally, ion exchange materials can be used to prepare immobilized,adsorbed co-crystals and thus effect controlled delivery of the drug.Examples of specific anion exchangers include, but are not limited to,Duolite® A568 and Duolite® AP143 (Rohm & Haas, Spring House, Pa. USA).

One embodiment of the invention encompasses a unit dosage form whichcomprises a pharmaceutically acceptable co-crystal, or a solvate,hydrate, dehydrate, anhydrous, or amorphous form thereof, and one ormore pharmaceutically acceptable excipients or diluents, wherein thepharmaceutical composition, medicament or dosage form is formulated forcontrolled-release. Specific dosage forms utilize an osmotic drugdelivery system.

A particular and well-known osmotic drug delivery system is referred toas OROS® (Alza Corporation, Mountain View, Calif. USA). This technologycan readily be adapted for the delivery of compounds and compositions ofthe invention. Various aspects of the technology are disclosed in U.S.Pat. Nos. 6,375,978 B1; 6,368,626 B1; 6,342,249 B1; 6,333,050 B2;6,287,295 B1; 6,283,953 B1; 6,270,787 B1; 6,245,357 B1; and 6,132,420;each of which is incorporated herein by reference. Specific adaptationsof OROS® that can be used to administer compounds and compositions ofthe invention include, but are not limited to, the OROS® Push-Pull™,Delayed Push-Pull™, Multi-Layer Push-Pull™, and Push-Stick™ Systems, allof which are well known. See, e.g., http://www.alza.com. AdditionalOROS® systems that can be used for the controlled oral delivery ofcompounds and compositions of the invention include OROS®-CT andL-OROS®. Id.; see also, Delivery Times, vol. II, issue II (AlzaCorporation).

Conventional OROS® oral dosage forms are made by compressing a drugpowder (e.g. co-crystal) into a hard tablet, coating the tablet withcellulose derivatives to form a semi-permeable membrane, and thendrilling an orifice in the coating (e.g., with a laser). Kim, Cherng-ju,Controlled Release Dosage Form Design, 231-238 (Technomic Publishing,Lancaster, Pa.: 2000). The advantage of such dosage forms is that thedelivery rate of the drug is not influenced by physiological orexperimental conditions. Even a drug with a pH-dependent solubility canbe delivered at a constant rate regardless of the pH of the deliverymedium. But because these advantages are provided by a build-up ofosmotic pressure within the dosage form after administration,conventional OROS® drug delivery systems cannot be used to effectivelydeliver drugs with low water solubility. Id. at 234. Because co-crystalsof this invention can be far more soluble in water than modafinilitself, they are well suited for osmotic-based delivery to patients.This invention does, however, encompass the incorporation ofconventional crystalline modafinil (e.g. pure modafinil withoutco-crystal former), and isomers and isomeric mixtures thereof, intoOROS® dosage forms.

A specific dosage form of the invention comprises: a wall defining acavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a dry orsubstantially dry state drug layer located within the cavity adjacent tothe exit orifice and in direct or indirect contacting relationship withthe expandable layer; and a flow-promoting layer interposed between theinner surface of the wall and at least the external surface of the druglayer located within the cavity, wherein the drug layer comprises aco-crystal, or a solvate, hydrate, dehydrate, anhydrous, or amorphousform thereof. See U.S. Pat. No. 6,368,626, the entirety of which isincorporated herein by reference.

Another specific dosage form of the invention comprises: a wall defininga cavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a drug layerlocated within the cavity adjacent the exit orifice and in direct orindirect contacting relationship with the expandable layer; the druglayer comprising a liquid, active agent formulation absorbed in porousparticles, the porous particles being adapted to resist compactionforces sufficient to form a compacted drug layer without significantexudation of the liquid, active agent formulation, the dosage formoptionally having a placebo layer between the exit orifice and the druglayer, wherein the active agent formulation comprises a co-crystal, or asolvate, hydrate, dehydrate, anhydrous, or amorphous form thereof. SeeU.S. Pat. No. 6,342,249, the entirety of which is incorporated herein byreference.

In another embodiment, a pharmaceutical composition or medicamentcomprises a mixture of a novel form of modafinil of the presentinvention (e.g., a co-crystal) and the free form of modafinil. Thisembodiment can be used, for example, as a controlled-, sustained-, orextended-release dosage form. In another embodiment, an extended-releasedosage form comprises free form modafinil and a co-crystal or a solvateof the present invention. Such an extended-release dosage form containsmodafinil in a form (e.g. modafinil:malonic acid co-crystal) which has agreater bioavailability than that of free form modafinil. In addition,the C_(max) of such a form can be greater than that of free formmodafinil, facilitating a therapeutic effect with longer duration thanfree form modafinil alone.

In another embodiment, a pharmaceutical composition or medicamentcomprises a modified release profile of one or more of racemicmodafinil, R-(−)-modafinil, and S-(+)-modafinil. The modified releaseprofile can comprise, for example, two or more maxima of plasmaconcentration, such as a dual-release profile. Such a modified releaseprofile may aid a patient treated with a composition or medicament ofthe present invention who experiences loss of wakefulness in theafternoon, for example. A second “burst” or release of API at least 2,3, 4, 5, or 6 hours after administration may help to overcome such aneffect. In another embodiment, a pharmaceutical composition ormedicament comprising a small loading dose released immediatelyfollowing administration can be employed, followed by an approximatezero-order release profile over the following 2, 3, 4, 5, or 6 hours. Insuch a composition, peak plasma levels can be reached at about midday.

In another embodiment, a pharmaceutical composition or medicamentcomprising a modified release profile of modafinil can compriseR-(−)-modafinil and S-(+)-modafinil wherein the R-(−)-modafinil providesan initial increase (initial C_(max) due to R-(−)-modafinil) in plasmaconcentration and the S-(+)-modafinil provides a delayed increase(subsequent C, due to S-(+)-modafinil) in plasma concentration. Thedelayed increase in C_(max) due to S-(+)-modafinil can be 2, 3, 4, 5, 6hours or more after the initial C_(max) due to R-(−)-modafinil. Inanother embodiment, the delayed C_(max) is approximately equal to theinitial C_(max). In another embodiment, the delayed C_(max) is greaterthan the initial C_(max). In another embodiment, the delayed C_(max) isless than the initial C_(max). In another embodiment, the delayedC_(max) is due to racemic modafinil, instead of S-(+)-modafinil. Inanother embodiment, the delayed C_(max) is due to R-(−)-modafinil,instead of S-(+)-modafinil. In another embodiment, the initial C_(max)is due to racemic modafinil, instead of R-(−)-modafinil. In anotherembodiment, the initial C_(max) is due to S-(+)-modafinil, instead ofR-(−)-modafinil. In another embodiment, the modified release profile has3, 4, 5, or more “bursts” in plasma concentration.

In another embodiment, a pharmaceutical composition or medicamentcomprising a modified release profile of modafinil wherein one or moreof racemic modafinil, R-(−)-modafinil, or S-(+)-modafinil are present inthe form of a co-crystal, solvate, free form, or a polymorph thereof.

In another embodiment, a pharmaceutical composition or medicamentcomprising a modified release profile wherein R-(−)-modafinil is used inan oral formulation. Such a composition can minimize first-passmetabolism of modafinil to the sulfone. In another embodiment, apharmaceutical composition or medicament comprising a modified releaseprofile wherein racemic modafinil is used in an oral formulation. Inanother embodiment, a pharmaceutical composition or medicamentcomprising a modified release profile wherein S-(+)-modafinil is used inan oral formulation. In another embodiment, a pharmaceutical compositionor medicament comprising a modified release profile wherein racemicmodafinil and R-(−)-modafinil are used in an oral formulation. Inanother embodiment, a pharmaceutical composition or medicamentcomprising a modified release profile wherein racemic modafinil andS-(+)-modafinil are used in an oral formulation. In another embodiment,a pharmaceutical composition or medicament comprising a modified releaseprofile wherein S-(+)-modafinil and R-(−)-modafinil are used in an oralformulation. In another embodiment, a pharmaceutical composition ormedicament comprising a modified release profile wherein racemicmodafinil, S-(+)-modafinil and R-(−)-modafinil are used in an oralformulation.

In another embodiment, a pharmaceutical composition or medicamentcomprising a modified release profile of modafinil is administeredtransdermally. Such a transdermal (TD) delivery can avoid first-passmetabolism. Additionally, a “pill-and-patch” strategy can be taken,where only a fraction of the daily dose is delivered through the skin togenerate basal systemic levels, onto which oral therapy is added toensure the wakefulness effect.

Excipients employed in pharmaceutical compositions and medicaments ofthe present invention can be solids, semi-solids, liquids orcombinations thereof. Preferably, excipients are solids. Compositionsand medicaments of the invention containing excipients can be preparedby known technique of pharmacy that comprises admixing an excipient withan API or therapeutic agent. A pharmaceutical composition or medicamentof the invention contains a desired amount of API per dose unit and, ifintended for oral administration, can be in the form, for example, of atablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, adispensable powder, granules, a suspension, an elixir, a dispersion, aliquid, or any other form reasonably adapted for such administration. Ifintended for parenteral administration, it can be in the form, forexample, of a suspension or transdermal patch. If intended for rectaladministration, it can be in the form, for example, of a suppository.Presently preferred are oral dosage forms that are discrete dose unitseach containing a predetermined amount of the API, such as tablets orcapsules.

Non-limiting examples follow of excipients that can be used to preparepharmaceutical compositions or medicaments of the invention.

Pharmaceutical compositions and medicaments of the invention optionallycomprise one or more pharmaceutically acceptable carriers or diluents asexcipients. Suitable carriers or diluents illustratively include, butare not limited to, either individually or in combination, lactose,including anhydrous lactose and lactose monohydrate; starches, includingdirectly compressible starch and hydrolyzed starches (e.g., Celutab™ andEmdex™); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000)and dextrose monohydrate; dibasic calcium phosphate dihydrate;sucrose-based diluents; confectioner's sugar; monobasic calcium sulfatemonohydrate; calcium sulfate dihydrate; granular calcium lactatetrihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose;celluloses including microcrystalline cellulose, food grade sources ofalpha- and amorphous cellulose (e.g., RexcelJ), powdered cellulose,hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC);calcium carbonate; glycine; bentonite; block co-polymers;polyvinylpyrrolidone; and the like. Such carriers or diluents, ifpresent, constitute in total about 5% to about 99%, preferably about 10%to about 85%, and more preferably about 20% to about 80%, of the totalweight of the composition. The carrier, carriers, diluent, or diluentsselected preferably exhibit suitable flow properties and, where tabletsare desired, compressibility.

Lactose, mannitol, dibasic sodium phosphate, and microcrystallinecellulose (particularly Avicel PH microcrystalline cellulose such asAvicel PH 101), either individually or in combination, are preferreddiluents. These diluents are chemically compatible with APIs. The use ofextragranular microcrystalline cellulose (that is, microcrystallinecellulose added to a granulated composition) can be used to improvehardness (for tablets) and/or disintegration time. Lactose, especiallylactose monohydrate, is particularly preferred. Lactose typicallyprovides compositions having suitable release rates of APIs, stability,pre-compression flowability, and/or drying properties at a relativelylow diluent cost. It provides a high density substrate that aidsdensification during granulation (where wet granulation is employed) andtherefore improves blend flow properties and tablet properties.

Pharmaceutical compositions and medicaments of the invention optionallycomprise one or more pharmaceutically acceptable disintegrants asexcipients, particularly for tablet formulations. Suitable disintegrantsinclude, but are not limited to, either individually or in combination,starches, including sodium starch glycolate (e.g., Explotab™ of PenWest)and pregelatinized corn starches (e.g., National™ 1551 of NationalStarch and Chemical Company, National™ 1550, and Colocorn™ 1500), clays(e.g., Veegum™ HV of R. T. Vanderbilt), celluloses such as purifiedcellulose, microcrystalline cellulose, methylcellulose,carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellosesodium (e.g., Ac-Di-Sol™ of FMC), alginates, crospovidone, and gums suchas agar, guar, locust bean, karaya, pectin and tragacanth gums.

Disintegrants may be added at any suitable step during the preparationof the composition, particularly prior to granulation or during alubrication step prior to compression. Such disintegrants, if present,constitute in total about 0.2% to about 30%, preferably about 0.2% toabout 10%, and more preferably about 0.2% to about 5%, of the totalweight of the composition.

Croscarmellose sodium is a preferred disintegrant for tablet or capsuledisintegration, and, if present, preferably constitutes about 0.2% toabout 10%, more preferably about 0.2% to about 7%, and still morepreferably about 0.2% to about 5%, of the total weight of thecomposition. Croscarmellose sodium confers superior intragranulardisintegration capabilities to granulated pharmaceutical compositionsand medicaments of the present invention.

Pharmaceutical compositions and medicaments of the invention optionallycomprise one or more pharmaceutically acceptable binding agents oradhesives as excipients, particularly for tablet formulations. Suchbinding agents and adhesives preferably impart sufficient cohesion tothe powder being tableted to allow for normal processing operations suchas sizing, lubrication, compression and packaging, but still allow thetablet to disintegrate and the composition to be absorbed uponingestion. Such binding agents may also prevent or inhibitcrystallization or recrystallization of an API of the present inventiononce the salt has been dissolved in a solution. Suitable binding agentsand adhesives include, but are not limited to, either individually or incombination, acacia; tragacanth; sucrose; gelatin; glucose; starchessuch as, but not limited to, pregelatinized starches (e.g., National™1511 and National™ 1500); celluloses such as, but not limited to,methylcellulose and carmellose sodium (e.g., Tylose™); alginic acid andsalts of alginic acid; magnesium aluminum silicate; PEG; guar gum;polysaccharide acids; bentonites; povidone, for example povidone K-15,K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g.,Klucel™ of Aqualon); and ethylcellulose (e.g., Ethocel™ of the DowChemical Company). Such binding agents and/or adhesives, if present,constitute in total about 0.5% to about 25%, preferably about 0.75% toabout 15%, and more preferably about 1% to about 10%, of the totalweight of the pharmaceutical composition or medicament.

Many of the binding agents are polymers comprising amide, ester, ether,alcohol or ketone groups and, as such, are preferably included inpharmaceutical compositions and medicaments of the present invention.Polyvinylpyrrolidones such as povidone K-30 are especially preferred.Polymeric binding agents can have varying molecular weight, degrees ofcrosslinking, and grades of polymer. Polymeric binding agents can alsobe copolymers, such as block co-polymers that contain mixtures ofethylene oxide and propylene oxide units. Variation in these units'ratios in a given polymer affects properties and performance. Examplesof block co-polymers with varying compositions of block units arePoloxamer 188 and Poloxamer 237 (BASF Corporation).

Pharmaceutical compositions and medicaments of the invention optionallycomprise one or more pharmaceutically acceptable wetting agents asexcipients. Such wetting agents are preferably selected to maintain theAPI in close association with water, a condition that is believed toimprove bioavailability of the composition.

Non-limiting examples of surfactants that can be used as wetting agentsin pharmaceutical compositions and medicaments of the invention includequaternary ammonium compounds, for example benzalkonium chloride,benzethonium chloride and cetylpyridinium chloride, dioctyl sodiumsulfosuccinate, polyoxyethylene alkylphenyl ethers, for examplenonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethyleneand polyoxypropylene block copolymers), polyoxyethylene fatty acidglycerides and oils, for example polyoxyethylene (8) caprylic/capricmono- and diglycerides (e.g., Labrasol™ of Gattefosse), polyoxyethylene(35) castor oil and polyoxyethylene (40) hydrogenated castor oil;polyoxyethylene alkyl ethers, for example polyoxyethylene (20)cetostearyl ether, polyoxyethylene fatty acid esters, for examplepolyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, forexample polysorbate 20 and polysorbate 80 (e.g., Tween™ 80 of ICI),propylene glycol fatty acid esters, for example propylene glycol laurate(e.g., Lauroglycol™ of Gattefosse), sodium lauryl sulfate, fatty acidsand salts thereof, for example oleic acid, sodium oleate andtriethanolamine oleate, glyceryl fatty acid esters, for example glycerylmonostearate, sorbitan esters, for example sorbitan monolaurate,sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate,tyloxapol, and mixtures thereof. Such wetting agents, if present,constitute in total about 0.25% to about 15%, preferably about 0.4% toabout 10%, and more preferably about 0.5% to about 5%, of the totalweight of the pharmaceutical composition or medicament.

Wetting agents that are anionic surfactants are preferred. Sodium laurylsulfate is a particularly preferred wetting agent. Sodium laurylsulfate, if present, constitutes about 0.25% to about 7%, morepreferably about 0.4% to about 4%, and still more preferably about 0.5%to about 2%, of the total weight of the pharmaceutical composition ormedicament.

Pharmaceutical compositions and medicaments of the invention optionallycomprise one or more pharmaceutically acceptable lubricants (includinganti-adherents and/or glidants) as excipients. Suitable lubricantsinclude, but are not limited to, either individually or in combination,glyceryl behapate (e.g., Compritol™ 888 of Gattefosse); stearic acid andsalts thereof, including magnesium, calcium and sodium stearates;hydrogenated vegetable oils (e.g., Sterotex™ of Abitec); colloidalsilica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodiumfumarate; sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 andCarbowax™ 6000 of the Dow Chemical Company); sodium oleate; sodiumlauryl sulfate; and magnesium lauryl sulfate. Such lubricants, ifpresent, constitute in total about 0.1% to about 10%, preferably about0.2% to about 80%, and more preferably about 0.25% to about 5%, of thetotal weight of the pharmaceutical composition or medicament.

Magnesium stearate is a preferred lubricant used, for example, to reducefriction between the equipment and granulated mixture during compressionof tablet formulations.

Suitable anti-adherents include, but are not limited to, talc,cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates.Talc is a preferred anti-adherent or glidant used, for example, toreduce formulation sticking to equipment surfaces and also to reducestatic in the blend. Talc, if present, constitutes about 0.1% to about10%, more preferably about 0.25% to about 5%, and still more preferablyabout 0.5% to about 2%, of the total weight of the pharmaceuticalcomposition or medicament.

Glidants can be used to promote powder flow of a solid formulation.Suitable glidants include, but are not limited to, colloidal silicondioxide, starch, talc, tribasic calcium phosphate, powdered celluloseand magnesium trisilicate. Colloidal silicon dioxide is particularlypreferred.

Other excipients such as colorants, flavors and sweeteners are known inthe pharmaceutical art and can be used in pharmaceutical compositionsand medicaments of the present invention. Tablets can be coated, forexample with an enteric coating, or uncoated. Compositions of theinvention can further comprise, for example, buffering agents.

Optionally, one or more effervescent agents can be used as disintegrantsand/or to enhance organoleptic properties of pharmaceutical compositionsand medicaments of the invention. When present in pharmaceuticalcompositions and medicaments of the invention to promote dosage formdisintegration, one or more effervescent agents are preferably presentin a total amount of about 30% to about 75%, and preferably about 45% toabout 70%, for example about 60%, by weight of the pharmaceuticalcomposition or medicament.

According to a particularly preferred embodiment of the invention, aneffervescent agent, present in a solid dosage form in an amount lessthan that effective to promote disintegration of the dosage form,provides improved dispersion of the API in an aqueous medium. Withoutbeing bound by theory, it is believed that the effervescent agent iseffective to accelerate dispersion of the API, from the dosage form inthe gastrointestinal tract, thereby further enhancing absorption andrapid onset of therapeutic effect. When present in a pharmaceuticalcomposition or medicament of the invention to promoteintragastrointestinal dispersion but not to enhance disintegration, aneffervescent agent is preferably present in an amount of about 1% toabout 20%, more preferably about 2.5% to about 15%, and still morepreferably about 5% to about 10%, by weight of the pharmaceuticalcomposition or medicament.

An “effervescent agent” herein is an agent comprising one or morecompounds which, acting together or individually, evolve a gas oncontact with water. The gas evolved is generally oxygen or, mostcommonly, carbon dioxide. Preferred effervescent agents comprise an acidand a base that react in the presence of water to generate carbondioxide gas. Preferably, the base comprises an alkali metal or alkalineearth metal carbonate or bicarbonate and the acid comprises an aliphaticcarboxylic acid.

Non-limiting examples of suitable bases as components of effervescentagents useful in the invention include carbonate salts (e.g., calciumcarbonate), bicarbonate salts (e.g., sodium bicarbonate),sesquicarbonate salts, and mixtures thereof. Calcium carbonate is apreferred base.

Non-limiting examples of suitable acids as components of effervescentagents and/or solid acids useful in the invention include citric acid,tartaric acid (as D-, L-, or D/L-tartaric acid), malic acid, maleicacid, fumaric acid, adipic acid, succinic acid, acid anhydrides of suchacids, acid salts of such acids, and mixtures thereof. Citric acid is apreferred acid.

In a preferred embodiment of the invention, where the effervescent agentcomprises an acid and a base, the weight ratio of the acid to the baseis about 1:100 to about 100:1, more preferably about 1:50 to about 50:1,and still more preferably about 1:10 to about 10:1. In a furtherpreferred embodiment of the invention, where the effervescent agentcomprises an acid and a base, the ratio of the acid to the base isapproximately stoichiometric.

Excipients which solubilize metal salts of APIs typically have bothhydrophilic and hydrophobic regions, or are preferably amphiphilic orhave amphiphilic regions. One type of amphiphilic orpartially-amphiphilic excipient comprises an amphiphilic polymer or isan amphiphilic polymer. A specific amphiphilic polymer is a polyalkyleneglycol, which is commonly comprised of ethylene glycol and/or propyleneglycol subunits. Such polyalkylene glycols can be esterified at theirtermini by a carboxylic acid, ester, acid anhyride or other suitablemoiety. Examples of such excipients include poloxamers (symmetric blockcopolymers of ethylene glycol and propylene glycol; e.g., poloxamer237), polyalkyene glycolated esters of tocopherol (including estersformed from a di- or multi-functional carboxylic acid; e.g.,d-alpha-tocopherol polyethylene glycol-1000 succinate), andmacrogolglycerides (formed by alcoholysis of an oil and esterificationof a polyalkylene glycol to produce a mixture of mono-, di- andtri-glycerides and mono- and di-esters; e.g., stearoyl macrogol-32glycerides). Such pharmaceutical compositions and medicaments areadvantageously administered orally.

Pharmaceutical compositions and medicaments of the present invention cancomprise about 10% to about 50%, about 25% to about 50%, about 30% toabout 45%, or about 30% to about 35% by weight of API; about 10% toabout 50%, about 25% to about 50%, about 30% to about 45%, or about 30%to about 35% by weight of a an excipient which inhibits crystallization;and about 5% to about 50%, about 10% to about 40%, about 15% to about35%, or about 30% to about 35% by weight of a binding agent. In oneexample, the weight ratio of the API to the excipient which inhibitscrystallization to binding agent is about 1 to 1 to 1.

Solid dosage forms of the invention can be prepared by any suitableprocess, not limited to processes described herein.

An illustrative process comprises (a) a step of blending a salt of theinvention with one or more excipients to form a blend, and (b) a step oftableting or encapsulating the blend to form tablets or capsules,respectively.

In a preferred process, solid dosage forms are prepared by a processcomprising (a) a step of blending an API salt of the invention with oneor more excipients to form a blend, (b) a step of granulating the blendto form a granulate, and (c) a step of tableting or encapsulating theblend to form tablets or capsules respectively. Step (b) can beaccomplished by any dry or wet granulation technique known in the art,but is preferably a dry granulation step. A salt of the presentinvention is advantageously granulated to form particles of about 1micrometer to about 100 micrometer, about 5 micrometer to about 50micrometer, or about 10 micrometer to about 25 micrometer. One or morediluents, one or more disintegrants and one or more binding agents arepreferably added, for example in the blending step, a wetting agent canoptionally be added, for example in the granulating step, and one ormore disintegrants are preferably added after granulating but beforetableting or encapsulating. A lubricant is preferably added beforetableting. Blending and granulating can be performed independently underlow or high shear. A process is preferably selected that forms agranulate that is uniform in API content, that readily disintegrates,that flows with sufficient ease so that weight variation can be reliablycontrolled during capsule filling or tableting, and that is dense enoughin bulk so that a batch can be processed in the selected equipment andindividual doses fit into the specified capsules or tablet dies.

In an alternative embodiment, solid dosage forms are prepared by aprocess that includes a spray drying step, wherein the API is suspendedwith one or more excipients in one or more sprayable liquids, preferablya non-protic (e.g., non-aqueous or non-alcoholic) sprayable liquid, andthen is rapidly spray dried over a current of warm air.

A granulate or spray dried powder resulting from any of the aboveillustrative processes can be compressed or molded to prepare tablets orencapsulated to prepare capsules. Conventional tableting andencapsulation techniques known in the art can be employed. Where coatedtablets are desired, conventional coating techniques are suitable.

Excipients for tablet compositions of the invention are preferablyselected to provide a disintegration time of less than about 30 minutes,preferably about 25 minutes or less, more preferably about 20 minutes orless, and still more preferably about 15 minutes or less, in a standarddisintegration assay.

In another embodiment of the present invention, a pharmaceuticalcomposition or medicament comprising modafinil and an additional API canbe prepared. The modafinil and the additional API can be in the form ofa co-crystal, or may be included as a mixture or a combination of activepharmaceutical ingredients. For example, a composition can comprisemodafinil and caffeine as a combination. A composition comprisingmodafinil and caffeine can be used as a therapeutic agent to treat thesame conditions as modafinil. In such a composition comprising modafiniland caffeine, the caffeine can yield a quick release characteristic(small T_(max) relative to modafinil) to the dissolution profile whilethe modafinil causes the therapeutic effect to be present for hoursafter administration. For example, the T_(max) of caffeine may be 0.001,0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8 times that ofmodafinil. Combination therapies comprise the administration of two ormore APIs in the same formulation, or in two or more co-administeredformulations. The APIs can be administered together at the same time, orindividually at specified intervals.

Uses for modafinil are well known in the art and include the treatmentof narcolepsy, multiple sclerosis related fatigue, infertility, eatingdisorders, attention deficit hyperactivity disorder (ADHD), Parkinson'sdisease, incontinence, sleep apnea, or myopathies. In anotherembodiment, any one or more of the modafinil compositions of the presentinvention may be used in the treatment of one or more of the aboveconditions. The dosage and administration for modafinil compositions ofthe present invention can be determined using routine methods in the artbut will generally fall between about 50 and about 700 mg/day.

In another embodiment, a composition of the present invention can beadministered to a mammal via an injection. Injections include, but arenot limited to, intravenous, subcutaneous, and intramuscular injections.In another embodiment, a composition of the present invention isformulated for injection into a mammal in need of therapeutic effect.

EXAMPLES

General Methods for the Preparation of Co-Crystals

a) High Throughput Crystallization Using the CrystalMax® Platform

CrystalMax® comprises a sequence of automated, integrated highthroughput robotic stations capable of rapid generation, identificationand characterization of polymorphs, salts, and co-crystals of APIs andAPI candidates. Worksheet generation and combinatorial mixture design iscarried out using proprietary design software Architect™. Typically, anAPI or an API candidate is dispensed from an organic solvent into tubesand dried under a stream of nitrogen. Salts and/or co-crystal formersmay also be dispensed and dried in the same fashion. Water and organicsolvents may be combinatorially dispensed into the tubes using amulti-channel dispenser. Each tube in a 96-tube array is then sealedwithin 15 seconds of combinatorial dispensing to avoid solventevaporation. The mixtures are then rendered supersaturated by heating to70 degrees C. for 2 hours followed by a 1 degree C./minute cooling rampto 5 degrees C. Optical checks are then conducted to detect crystalsand/or solid material. Once a solid has been identified in a tube, it isisolated through aspiration and drying. Raman spectra are then obtainedon the solids and cluster classification of the spectral patterns isperformed using proprietary software (Inquire™).

b) Crystallization from Solution

Co-crystals may be obtained by dissolving the separate components in asolvent and adding one to the other. The co-crystal may then precipitateor crystallize as the solvent mixture is evaporated slowly. Theco-crystal may also be obtained by dissolving the two components in thesame solvent or a mixture of solvents. The co-crystal may also beobtained by seeding a saturated solution of the two components andseeding with a ground mixture of the co-crystal.

c) Crystallization from the Melt (Co-Melting)

A co-crystal may be obtained by melting the two components together(i.e., co-melting) and allowing recrystallization to occur. In somecases, an anti-solvent may be added to facilitate crystallization.

d) Thermal Microscopy

A co-crystal may be obtained by melting the higher melting component ona glass slide and allowing it to recrystallize. The second component isthen melted and is also allowed to recrystallize. The co-crystal mayform as a separated phase/band in between the eutectic bands of the twooriginal components.

e) Mixing and/or Grinding

A co-crystal may be obtained by mixing or grinding two componentstogether in the solid state. For example, Example 12 describes thesynthesis of a modafinil:1-hydroxy-2-naphthoic acid co-crystal obtainedby milling with the addition of a small amount of an appropriate solvent(wet grinding). Similarly, Example 5 describes the synthesis of amodafinil:citric acid monohydrate co-crystal obtained by milling bothwith and without the addition of a small amount of an appropriatesolvent. In one embodiment, a co-crystal is prepared via milling orgrinding modafinil with a co-crystal former (dry grinding). In anotherembodiment, a co-crystal is prepared via milling or grinding modafinil,a co-crystal former, and a small amount of solvent (wet grinding).

In another embodiment, a co-crystal is prepared with the addition ofsolvent, without the addition of solvent, or both. Solvents used in sucha co-crystallization process can be, for example, but not limited to,acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, isopropylacetate, nitromethane, dichloromethane, chloroform, toluene, propyleneglycol, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), diethylether (ether), ethyl formate, hexane, acetonitrile, benzyl alcohol,water, or another organic solvent including alcohols.

f) Co-Sublimation

A co-crystal may be obtained by co-subliming a mixture of an API and aco-crystal former in the same sample cell as an intimate mixture eitherby heating, mixing or placing the mixture under vacuum. A co-crystal mayalso be obtained by co-sublimation using a Kneudsen apparatus where theAPI and the co-crystal former are contained in separate sample cells,connected to a single cold finger, each of the sample cells ismaintained at the same or different temperatures under a vaccumatmosphere in order to co-sublime the two components onto thecold-finger forming the desired co-crystal.

Analytical Methods

Differential scanning calorimetric (DSC) analysis of the samples wasperformed using a Q1000 Differential Scanning Calorimeter (TAInstruments, New Castle, Del., U.S.A.), which uses Advantage forQW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TAInstruments-Water LLC). In addition, the analysis software used wasUniversal Analysis 2000 for Windows 95/98/2000/NT, version 3.1E; Build3.1.0.40 (2001 TA Instruments-Water LLC).

For the DSC analysis, the purge gas used was dry nitrogen, the referencematerial was an empty aluminum pan that was crimped, and the samplepurge was 50 mL/minute.

DSC analysis of the sample was performed by placing the modafinil samplein an aluminum pan with a crimped pan closure. The starting temperaturewas typically 20 degrees C. with a heating rate of 10 degrees C./minute,and the ending temperature was 200 degrees C. All reported DSCtransitions represent the temperature of endothermic or exothermictransition at their respective peaks with an error of +/−2 degrees C.,unless otherwise indicated.

Thermogravimetric analysis (TGA) of samples was performed using a Q500Thermogravimetric Analyzer (TA Instruments, New Castle, Del., U.S.A.),which uses Advantage for QW-Series, version 1.0.0.78, Thermal AdvantageRelease 2.0 (2001 TA Instruments-Water LLC). In addition, the analysissoftware used was Universal Analysis p000 for Windows 95/98/2000/NT,version 3.1E; Build 3.1.0.40 (2001 TA Instruments-Water LLC).

For the TGA experiments, the purge gas used was dry nitrogen, thebalance purge was 40 mL/minute N₂, and the sample purge was 60 mL/minuteN₂.

TGA was performed on the sample by placing the modafinil sample in aplatinum pan. The starting temperature was typically 20 degrees C. witha heating rate of 10 degrees C./minute, and the ending temperature was300 degrees C.

A powder X-ray diffraction (PXRD) pattern for the samples was obtainedusing a D/Max Rapid, Contact (Rigaku/MSC, The Woodlands, Tex., U.S.A.),which uses as its control software RINT Rapid Control Software, RigakuRapid/XRD, version 1.0.0 (1999 Rigaku Co.). In addition, the analysissoftware used were RINT Rapid display software, version 1.18(Rigaku/MSC), and JADE XRD Pattern Processing, versions 5.0 and 6.0((1995-2002, Materials Data, Inc.).

For the PXRD analysis, the acquisition parameters were as follows:source was Cu with a K line at 1.5406 Å; x-y stage was manual;collimator size was 0.3 mm; capillary tube (Charles Supper Company,Natick, Mass., U.S.A.) was 0.3 mm ID; reflection mode was used; thepower to the X-ray tube was 46 kV; the current to the X-ray tube was 40mA; the omega-axis was oscillating in a range of 0-5 degrees at a speedof 1 degree/minute; the phi-axis was spinning at an angle of 360 degreesat a speed of 2 degrees/second; 0.3 mm collimator; the collection timewas 60 minutes; the temperature was room temperature; and the heater wasnot used. The sample was presented to the X-ray source in a boron richglass capillary.

In addition, the analysis parameters were as follows: the integration2-theta range was 2-60 degrees; the integration chi range was 0-360degrees; the number of chi segments was 1; the step size used was 0.02;the integration utility was cylint; normalization was used; dark countswere 8; omega offset was 180; and chi and phi offsets were 0.

PXRD diffractograms were also acquired via the Bruker AXS D8 DiscoverX-ray Diffractometer. This instrument was equipped with GADDS™ (GeneralArea Diffraction Detection System), a Bruker AXS HI-STAR Area Detectorat a distance of 15.05 cm as per system calibration, a copper source(Cu/K_(α) 1.54056 angstroms), automated x-y-z stage, and 0.5 mmcollimator. The sample was compacted into pellet form and mounted on thex-y-z stage. A diffractogram was acquired under ambient conditions (25degrees C.) at a powder setting of 40 kV and 40 mA in reflection modewhile the sample remained stationary. The exposure time was varied andspecified for each sample. The diffractogram obtained underwent aspatial remapping procedure to account for the geometrical pincushiondistortion of the area detector then integrated along chi from −118.8 to−61.8 degrees and 2-theta 2.1-37 degrees at a step size of 0.02 degreeswith normalization set to bin normalize.

The relative intensity of peaks in a diffractogram is not necessarily alimitation of the PXRD pattern because peak intensity can vary fromsample to sample, e.g., due to crystalline impurities. Further, theangles of each peak can vary by about +/−0.1 degrees, preferably+/−0.05. The entire pattern or most of the pattern peaks may also shiftby about +/−0.1 degrees to about +/−0.2 degrees due to differences incalibration, settings, and other variations from instrument toinstrument and from operator to operator. All reported PXRD peaks in theFigures, Examples, and elsewhere herein are reported with an error ofabout ±0.1 degrees 2-theta.

For PXRD data herein, including Tables and Figures, each composition ofthe present invention may be characterized by any one, any two, anythree, any four, any five, any six, any seven, or any eight or more ofthe 2 theta angle peaks. Any one, two, three, four, five, or six DSCtransitions can also be used to characterize the compositions of thepresent invention. The different combinations of the PXRD peaks and theDSC transitions can also be used to characterize the compositions.

Thermal (hotstage) microscopy was completed on a Zeiss Axioplan 2microscope equipped with a Mettler Toledo FP90 controller. The hotstageused was a Mettler Toledo FP82HT. All melting point determinations werecompleted by placing the sample on a microscope slide and covered with acoverslip. The initial temperature was set at 30 degrees C. and thetemperature was increased at a rate of 10 degrees C./minute. Melting wasobserved through a 5× microscope objective.

HPLC Method: (adapted from Donovan et al. Therapeutic Drug Monitoring25:197-202.

Column: Astec Cyclobond I 2000 RSP 250×4.6 mm (Part No. 411121)

Mobile Phase

-   -   A: 20 mM sodium phosphate, pH 3.0    -   B: 70:30 mobile phase A:acetonitrile

Flow Rate: 1.0 mL/min (˜1500 PSI)

Flow Program: gradient

Run Time: 35 minutes

Detection: UV @ 225 nm

Injection Volume: 10 microliters

Column Temperature: 30+/−1 degrees C.

Standard diluent: 90:10 (v/v) Mobile Phase A:acetonitrile

Needle wash: acetonitrile

Purge solvent & seal wash: 90:10 (v/v) water:acetonitrile

Mobile Phase Preparation:

-   1. Prep 1 M sodium phosphate monobasic: dissolve 120 g of sodium    phosphate monobasic in water and make up to 1000 mL; filter.-   2. Prep Mobile Phase A (20 mM sodium phosphate, pH 3.0): for each    liter, dilute 20 mL 1 M sodium phosphate to 1000 mL with water;    adjust pH to 3.0 with phosphoric acid.-   3. Prep Mobile Phase B (70:30 (v/v) 20 mM sodium phosphate, pH    3.0:acetonitrile): for each liter, mix 700 mL Mobile Phase A and 300    mL of acetonitrile.    Sample Prep:-   1. Dissolve samples in 90:10 (v/v) 20 mM sodium phosphate, pH    3.0:acetonitrile to an approximate concentration of 20 micrograms/mL    Raman Acquisitions

The sample was either left in the glass vial in which it was processedor an aliquot of the sample was transferred to a glass slide. The glassvial or slide was positioned in the sample chamber. The measurement wasmade using an Almega™ Dispersive Raman (Almega™ Dispersive Raman,Thermo-Nicolet, 5225 Verona Road, Madison, Wis. 53711-4495) systemfitted with a 785 nm laser source. The sample was manually brought intofocus using the microscope portion of the apparatus with a 10× powerobjective (unless otherwise noted), thus directing the laser onto thesurface of the sample. The spectrum was acquired using the parameters,outlined in Table A. Exposure times and number of exposures may vary;changes to parameters will be indicated for each acquisition.) TABLE ARaman Spectral acquisition parameters Parameter Setting Used Exposuretime (s) 2.0 Number of exposures 10 Laser source wavelength (nm) 785Laser power (%) 100 Aperture shape pin hole Aperture size (um) 100Spectral range 104-3428 Grating position Single Temperature atacquisition (degrees C.) 24.0IR Acquisitions

IR spectra were obtained using Nexus™ 470 FT-IR, Thermo-Nicolet, 5225Verona Road, Madison, Wis. 53711-4495 and were analyzed with Control andAnalysis software: OMNIC, Version 6.0a, (C) Thermo-Nicolet, 1995-2004.

Data for the co-crystals are shown in Table IV and in the Figures.

Example 1

Racemic Modafinil:Malonic Acid Co-Crystal

To a solution containing racemic modafinil (150 mg, 0.549 mmol) inacetic acid (600 microliters) was added malonic acid (114.9 mg, 1.104mmol). The mixture was then heated on a hotplate at 67 degrees C. untilall material dissolved. The solution was then dried under a flow ofnitrogen to give a 1:1 modafinil:malonic acid co-crystal as a colorlesssolid. The solid material was characterized using PXRD. The material wasthen dried further under a flow of nitrogen overnight to give the samematerial with a slight excess of malonic acid. The colorless solid wascharacterized using PXRD (Bruker), DSC, TGA, IR and Raman spectroscopy.PXRD data for the modafinil:malonic acid (1:1) co-crystal are listed inTable IV, and the diffractogram is shown in FIG. 1 (Data ascollected/received). DSC showed an endothermic transition at about 106degrees C., and the thermogram is shown in FIG. 2. TGA thermogram isshown in FIG. 3. FIGS. 4A and 4B show a Raman spectrum of themodafinil:malonic acid co-crystal and three Raman spectra of modafinil,malonic acid, and the co-crystal, respectively. FIGS. 5A and 5B show anIR spectrum of the modafinil:malonic acid co-crystal and three IRspectra of modafinil, malonic acid, and the co-crystal, respectively.The modafinil:malonic acid co-crystal can be characterized by any one,any two, any three, any four, any five, or any six or more of the peaksin FIG. 1 including, but not limited to, 5.00, 9.17, 10.08, 16.81,18.26, 19.43, 21.36, 21.94, 22.77, 24.49, 25.63, 26.37, and 28.45degrees 2-theta.

The modafinil:malonic acid co-crystal was also prepared by grinding theAPI and co-crystal former together. Racemic modafinil (2.50 g, 0.009mol) and malonic acid (1.01 g, 0.0097 mmol) were mixed in a large mortarand pestle over a period of seven days (malonic acid added in incrementsover 7 days with about a 1:1.05 ratio made on the first day andincrements added over the next seven days which resulted in a 1:2modafinil:malonic acid ratio). The mixture was ground for 45 minutesinitially and 20 minutes each time more malonic acid was added. On theseventh day the mixture of co-crystal and starting components was heatedin a sealed 20 mL vial at 80 degrees C. for about 35 minutes tofacilitate completion of the co-crystal formation. PXRD analysis(Bruker) of the resultant material was completed, and is shown in FIG.6A (data as received). The modafinil:malonic acid co-crystal can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 6A including, but not limited to, 5.08,9.28, 16.81, 18.27, 19.45, 21.39, 21.99, 22.83, 23.50, 24.58, 25.12, and28.49 degrees 2-theta. DSC thermogram for the co-crystal shows, in FIG.6B, an endothermic transition at about 116 degrees C. Single crystaldata of the modafinil:malonic acid co-crystal were acquired and arereported below. FIG. 7 shows a packing diagram of the modafinil:malonicacid.

Crystal data: C₁₈H₁₉NO₆S, M=377.40, monoclinic C2/c; a=18.728(8)angstroms, b=5.480(2) angstroms, c=33.894(13) angstroms, alpha=90degrees, beta=91.864(9) degrees, gamma=90 degrees, T=100(2) K, Z=8,D_(c)=1.442 Mg/m³, V=3477(2) cubic angstroms, λ=0.71073 angstroms, 6475reflections measured, 3307 unique (R_(int)=0.1567). Final residuals wereR₁=0.1598, wR₂=0.3301 for I>2sigma(I), and R₁=0.2544, wR₂=0.3740 for all3307 data.

Other methods were also used to prepare the modafinil:malonic acidco-crystal. A third preparation was performed by placing modafinil (30mg, 0.0001 mol) and excess malonic acid in a stainless steel vial. 20microliters of acetone was added to the vial. The vial was then placedin a grinder (wig-1-bug, Bratt Technologies, 115V/60 Hz) and the solidmixture was milled for 5 minutes. The resultant powder was thencollected and characterized using PXRD and DSC. In yet anotherpreparation of the modafinil:malonic acid co-crystal, the thirdpreparation above was completed without the addition of solvent. All ofthe above methods with malonic acid were shown to yield the sameco-crystal via PXRD and DSC analysis.

Example 2

Racemic Modafinil:Glycolic Acid Co-Crystal

Racemic modafinil (1 mg, 0.0037 mmol) and glycolic acid (0.30 mg, 0.0037mmol) were dissolved in acetone (400 microliters). The solution wasallowed to evaporate to dryness and the resulting solid wascharacterized using PXRD (Rigaku). PXRD data for the modafinil:glycolicacid co-crystal are listed in Table IV. See FIGS. 8A and 8B. FIG. 5Ashows the PXRD diffractogram after subtraction of background noise. FIG.8B shows the raw PXRD data as collected.

An alternative method for the preparation of modafinil:glycolic acidco-crystals was also completed. To a solution of modafinil (1 mg, 0.0037mmol) dissolved in a mixture of acetone and methanol (3:1, 100microliters) was added glycolic acid (0.28 mg, 0.0037 mmol) dissolved inmethanol (50 microliters). The solvent was then evaporated to drynessunder a flow of nitrogen to give a mixture of the two startingcomponents. Acetone (200 microliters) was then added to the mixture andit was heated to 70 degrees C. and maintained at 70 degrees C. for 2hours. The sample was then cooled to 5 degrees C. and maintained at thattemperature for 1 day. After 1 day, the cap was removed from the vialand the solvent was evaporated to dryness to give a modafinil:glycolicacid co-crystal as a colorless solid. The modafinil:glycolic acidco-crystal was characterized by PXRD. The modafinil:glycolic acidco-crystal can be characterized by any one, any two, any three, anyfour, any five, or any six or more of the peaks in FIG. 8A including,but not limited to, 9.51, 14.91, 15.97, 19.01, 20.03, 21.59, 22.75,25.03, and 25.71 degrees 2-theta. The modafinil:glycolic acid co-crystalcan, likewise, be characterized by any one, any two, any three, anyfour, any five, or any six or more of the peaks in FIG. 8B including,but not limited to, 9.53, 14.93, 15.99, 19.05, 20.05, 21.61, 22.77, and25.05 degrees 2-theta.

Example 3

Racemic Modafinil:Maleic Acid Co-Crystal

To a solution containing modafinil (150 mg, 0.549 mmol) in acetic acid(600 microliters) was added maleic acid (30.7 mg, 0.264 mmol). Themixture was then heated on a hotplate at 67 degrees C. until allmaterial dissolved. The solution was then dried under a flow of nitrogento give a clear amorphous material. The amorphous material was stored ina sealed vial at room temperature. After 2 days, a solid material beganto form and and was collected and characterized to be a modafinil:maleicacid co-crystal using PXRD (Rigaku), as shown in FIGS. 9A and 9B. FIG.9A shows the PXRD diffractogram after subtraction of background noise.FIG. 9B shows the raw PXRD data. PXRD data for the modafinil:maleic acidco-crystal are listed in Table IV. The modafinil:maleic acid co-crystalcan be characterized by any one, any two, any three, any four, any five,or any six or more of the peaks in FIG. 9A including, but not limitedto, 4.69, 6.15, 9.61, 10.23, 15.65, 16.53, 17.19, 18.01, 19.97, 21.83,and 22.45 degrees 2-theta. The modafinil:maleic acid co-crystal can,likewise, be characterized by any one, any two, any three, any four, anyfive, or any six or more of the peaks in FIG. 9B including, but notlimited to, 4.69, 6.17, 9.63, 10.25, 15.67, 16.53, 17.21, 18.05, 19.99,21.85, and 22.47 degrees 2-theta.

Example 4

Racemic Modafinil:L-Tartaric Acid Co-Crystal

To a solution of racemic modafinil (10.12 mg, 0.037 mmol) in methanol (2mL) was added L-tartaric acid (5.83 mg, 0.039 mmol). The solution wasthen left to evaporate at room temperature to give a clear, viscousmaterial. The material was dried further under flowing nitrogen for 2days, and then placed in a vial and capped. After 6 days, a small amountof colorless solid formed. One day after the first solids are seenapproximately 60% of the remaining clear amorphous volume converted tothe solid form. A sample of this material was analyzed by PXRD (Bruker),as shown in FIG. 10. The modafinil:L-tartaric acid co-crystal can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 10 including, but not limited to, 6.10,7.36, 9.38, 14.33, 16.93, 17.98, 18.81, 20.15, 20.71, 22.49, and 25.04degrees 2-theta.

Example 5

Racemic Modafinil:Citric Acid Co-Crystal

Racemic modafinil (25.3 mg, 93 mmol) and citric acid monohydrate (26.8mg, 128 mmol) were ground together for 3 minutes. 1 mg of the resultingmixture was then dissolved in acetone (100 microliters) and heated to 70degrees C. and maintained at that temperature for 2 hours. The solutionwas then cooled to 5 degrees C. and was left at that temperature for 2days. After 2 days the cap was removed from the vial and one drop ofwater was added. The solvent was then evaporated to give amodafinil:citric acid monohydrate co-crystal as a colorless solid. Themodafinil:citric acid monohydrate co-crystal was characterized by PXRD(Rigaku), as shown in FIG. 11A (background subtracted). Themodafinil:citric acid co-crystal can be characterized by any one, anytwo, any three, any four, any five, or any six or more of the peaks inFIG. 11A including, but not limited to, 5.29, 7.29, 9.31, 12.41, 13.29,17.29, 17.97, 18.79, 21.37, and 23.01 degrees 2-theta.

Other methods were also used to prepare the modafinil:citric acidmonohydrate co-crystal. A second preparation was performed by placingmodafinil (30 mg, 0.0001 mol) and excess citric acid monohydrate in astainless steel vial. 20 microliters of acetone was added to the vial.The vial was then placed in a grinder (wig-1-bug, Bratt Technologies, II5V/60 Hz) and the solid mixture was milled for 5 minutes. The resultantpowder was then collected and characterized using PXRD and DSC. The DSCthermogram is shown in FIG. 11B. In yet another preparation of themodafinil:citric acid monohydrate co-crystal, the second preparationabove was completed without the addition of solvent. All of the abovemethods with citric acid monohydrate were shown to yield the sameco-crystal via PXRD and DSC analysis.

Example 6

Racemic Modafinil:Succinic Acid Co-Crystal

Racemic modafinil (25 mg, 90 mmol) and succinic acid (10.6 mg, 90 mmol)were placed in a glass vial and dissolved in methanol (20 microliters).The resulting solution was heated at 70 degrees C. for 2 hours and thencooled to 5 degrees C. and maintained at that temperature for 2 days.After 2 days, the cap was removed from the vial and the solvent wasevaporated at 65 degrees C. to give a 2:1 modafinil:succinic acidco-crystal as a colorless solid. The co-crystal is a 2:1 co-crystalcomprising two moles of modafinil for every mole of succinic acid. Themodafinil:succinic acid co-crystal was characterized by PXRD (Rigaku)and DSC, as shown in FIGS. 12A, 12B, and 13. FIG. 12A shows the PXRDdiffractogram after subtraction of background noise. FIG. 12B shows theraw PXRD data. FIG. 13 shows the DSC thermogram.

An alternative method for the preparation of modafinil:succinic acidco-crystals was also completed. To racemic modafinil (49.7 mg, 0.182mmol) and succinic acid (21.6 mg, 0.182 mmol) in a round bottom flaskwas added methanol (1.5 mL). The mixture was then dissolved on ahotplate at 65 degress C. Seed crystals of modafinil:succinic acidco-crystal from the above preparation were then added to the flask. Themethanol was then evaporated using a rotary evaporator and a 65 degreesC. hot water bath to give the modafinil:succinic acid co-crystal as acolorless solid. PXRD (Rigaku) of the collected solid confirms thesynthesis of the modafinil:succinic acid co-crystal. Themodafinil:succinic acid co-crystal can be characterized by any one, anytwo, any three, any four, any five, or any six or more of the peaks inFIG. 12A including, but not limited to, 5.45, 9.93, 15.85, 17.97, 18.73,19.95, 21.33, 21.93, 23.01, and 25.11 degrees 2-theta. Themodafinil:succinic acid co-crystal can, likewise, be characterized byany one, any two, any three, any four, any five, or any six or more ofthe peaks in FIG. 12B including, but not limited to, 5.45, 9.93, 15.87,17.99, 18.75, 19.95, 21.95, 23.03, and 25.07 degrees 2-theta. Singlecrystal data of the modafinil:succinic acid co-crystal were acquired andare reported below. FIG. 14 shows a packing diagram of themodafinil:succinic acid co-crystal.

Crystal data: C₁₇H₁₈NO₄S, triclinic P-1; a=5.672(4) angstroms,b=8.719(6) angstroms, c=16.191(11) angstroms, alpha=93.807(14) degrees,beta=96.471(17) degrees, gamma=92.513(13) degrees, T=100(2) K, Z=2,D_(c)=1.392 Mg/m³, V=792.8(9) cubic angstroms, λ=0.71073 angstroms, 2448reflections measured, 1961 unique (R_(int)=0.0740). Final residuals wereR₁=0.1008, wR₂=0.2283 for I>2sigma(I), and R₁=0.1593, wR₂=0.2614 for all1961 data.

A third method was also used to prepare the modafinil:succinic acidco-crystal. This method was performed by placing modafinil (30 mg,0.0001 mol) and excess succinic acid in a stainless steel vial. 20microliters of acetone was added to the vial. The vial was then placedin a grinder (wig-1-bug, Bratt Technologies, 115V/60 Hz) and the solidmixture was milled for 5 minutes. The resultant powder was thencollected and characterized using PXRD and DSC. All of the above methodswith succinic acid were shown to yield the same co-crystal via PXRD andDSC analysis.

Example 7

Racemic Modafinil:DL-Tartaric Acid Co-Crystal

A suspsension of racemic modafinil (162 mg; 0.591 mmol) and DL-tartaricacid (462 mg; 3.08 mmol) in acetone (10 mL) was heated to reflux for 1minute. The undissolved DL-tartaric acid was filtered off while thesuspension was still hot through a 0.2 micrometer PTFE filter. Theremaining solution was allowed to cool to room temperature then to 0degrees C. for 1 hour. After 1 hour, large colorless crystals wereobserved. The mother liquor was decanted and the solid was allowed toair dry and was characterized by PXRD (Rigaku), as shown in FIG. 15. Themodafinil:DL-tartaric acid co-crystal can be characterized by any one,any two, any three, any four, any five, or any six or more of the peaksin FIG. 15 including, but not limited to, 4.75, 9.53, 10.07, 15.83,17.61, 19.37, 20.25, 21.53, 22.55, and 23.75 degrees 2-theta (ascollected).

Example 8

Racemic Modafinil:Fumaric Acid Co-Crystal (Form I)

Racemic modafinil (30 mg, 0.0001 mol) and fumaric acid (2.3 mg, 0.0002mol) were placed in a stainless steel vial. 20 microliters of acetonewas added to the vial. The vial was then placed in a grinder (wig-1-bug,Bratt Technologies, 115V/60 Hz) and the solid mixture was milled for 5minutes. The resultant powder was then collected and characterized asmodafinil:fumaric acid co-crystal (Form I) using PXRD (Rigaku), as shownin FIG. 16. The co-crystal is a 2:1 co-crystal comprising two moles ofmodafinil for every mole of fumaric acid. The modafinil:fumaric acidco-crystal (Form I) can be characterized by any one, any two, any three,any four, any five, or any six or more of the peaks in FIG. 16including, but not limited to, 5.45, 9.95, 10.91, 15.93, 18.03, 18.81,19.93, 20.25, 21.37, 21.95, 23.09, and 25.01 degrees 2-theta (ascollected). Single crystal data of the modafinil:fumaric acid co-crystal(Form I) were acquired and are reported below. FIG. 17 shows a packingdiagram of the modafinil:fumaric acid co-crystal (Form I).

Crystal data: C₁₇H₁₇NO₄S, M=331.38, triclinic P-1; a=5.7000(15)angstroms, b=8.735(2) angstroms, c=16.204(4) angstroms, alpha=93.972(6)degrees, beta=97.024(6) degrees, gamma=93.119(7) degrees, T=100(2) K,Z=2, D_(c)=1.381 Mg/m³, V=797.2(4) cubic angstroms, λ=0.71073 angstroms,4047 reflections measured, 2615 unique (R_(int)=0.0475). Final residualswere R₁=0.0784, wR₂=0.1584 for I>2sigma(I), and R₁=0.1154, wR₂=0.1821for all 2615 data.

Example 9

Racemic Modafinil:Fumaric Acid Co-Crystal (Form II)

Racemic modafinil (30 mg, 0.0001 mol) and fumaric acid (1.2 mg, 0.0001mol) were placed in a stainless steel vial. 20 microliters of acetonewas added to the vial. The vial was then placed in a grinder (wig-1-bug,Bratt Technologies, 115V/60 Hz) and the solid mixture was milled for 5minutes. The resultant powder was then collected and characterized asmodafinil:fumaric acid co-crystal (Form II) using PXRD (Rigaku), asshown in FIG. 18. The modafinil:fumaric acid co-crystal (Form II) can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 18 including, but not limited to, 6.47,8.57, 9.99, 13.89, 14.53, 16.45, 17.13, 17.51, 18.39, 20.05, 20.79,25.93, and 27.95 degrees 2-theta (as collected).

Example 10

Racemic Modafinil:Gentisic Acid Co-Crystal

Racemic modafinil (30 mg, 0.0001 mol) and gentisic acid (1.5 mg, 0.0001mol) were placed in a stainless steel vial. 20 microliters of acetonewas added to the vial. The vial was then placed in a grinder (wig-1-bug,Bratt Technologies, 115V/60 Hz) and the solid mixture was milled for 5minutes. The resultant powder was then collected and characterized usingPXRD (Bruker), as shown in FIG. 19. The modafinil:gentisic acidco-crystal can be characterized by any one, any two, any three, anyfour, any five, or any six or more of the peaks in FIG. 19 including,but not limited to, 6.96, 12.92, 14.76, 17.40, 18.26, 20.10, 20.94,23.46, and 24.36 degrees 2-theta (as collected).

Example 11

Racemic Modafinil:Oxalic Acid Co-Crystal

A preparation of modafinil:oxalic acid co-crystal was performed byplacing racemic modafinil (30 mg, 0.0001 mol) and oxalic acid (1-2 mg,0.0001-0.0002 mol) in a stainless steel vial. 20 microliters of acetonewas added to the vial. The vial was then placed in a grinder (wig-1-bug,Bratt Technologies, 11 5V/60 Hz) and the solid mixture was milled for 5minutes. The resultant powder was then collected and characterized usingPXRD (Bruker), as shown in FIG. 20. In another preparation of themodafinil:oxalic acid co-crystal, the preparation above was completedwithout the addition of solvent. Both methods were shown to yield thesame co-crystal via PXRD analysis. The modafinil:oxalic acid co-crystalcan be characterized by any one, any two, any three, any four, any five,or any six or more of the peaks in FIG. 20 including, but not limitedto, 5.98, 13.68, 14.80, 17.54, 19.68, 21.12, 21.86, and 28.90 degrees2-theta (as collected).

Example 12

Racemic Modafinil:1-Hydroxy-2-Naphthoic Acid Co-Crystal

Racemic modafinil (30 mg, 0.0001 mol) and 1-hydroxy-2-naphthoic acid (21mg, 0.0001 mol) were placed in a stainless steel vial. 20 microliters ofacetone was added to the vial. The vial was then placed in a grinder(wig-1-bug, Bratt Technologies, 115V/60 Hz) and the solid mixture wasmilled for 5 minutes. The resultant powder was then collected andcharacterized using PXRD (Bruker), as shown in FIG. 21. Themodafinil:1-hydroxy-2-naphthoic acid co-crystal can be characterized byany one, any two, any three, any four, any five, or any six or more ofthe peaks in FIG. 21 including, but not limited to, 5.72, 7.10, 11.48,14.16, 15.66, 17.92, 19.18, 20.26, 21.28, 21.94, 24.38, and 26.86degrees 2-theta (as collected). PXRD peaks at 10.05 and 26.36 degrees2-theta may be from excess co-crystal former.

Example 13

R-(−)-Modafinil:Malonic Acid Co-Crystal

R-(−)-modafinil:malonic acid co-crystal was prepared by grindingR-(−)-modafinil (29.7 mg, 0.109 mmol, 82.2 percent R-isomer) withmalonic acid (11.9 mg, 0.114 mmol). The ground mixture was then heatedto 80 degrees C. for 10 minutes. The powder was analyzed by PXRD(Bruker) and DSC, as shown in FIGS. 22 and 23, respectively. The PXRDpattern confirms that the co-crystal was made and shows manysimilarities to the PXRD pattern for the racemic modafinil:malonic acidco-crystal. The R-(−)-modafinil:malonic acid co-crystal can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 22 including, but not limited to, 5.04,9.26, 16.73, 18.23, 19.37, 21.90, 22.74, 24.44, and 25.67 degrees2-theta (data as collected). The DSC showed a melting range of111.5-114.7 degrees C. with a heat of fusion of 112.9 J/g.

Example 14

R-(−)-Modafinil:Succinic Acid Co-Crystal

R-(−)-modafinil:succinic acid co-crystal was prepared by grindingR-(−)-modafinil (30.9 mg, 0.113 mmol, 82.2 percent R-isomer) withsuccinic acid (14.8 mg, 0.125 mmol). The ground mixture was then heatedto 145 degrees C. for 5 minutes. The powder was analyzed by PXRD(Bruker) and DSC, as shown in FIGS. 24 and 25, respectively. The PXRDpattern confirms that the co-crystal was made and shows manysimilarities to the PXRD pattern for the racemic modafinil:succinic acidco-crystal made from solution. The R-(−)-modafinil:succinic acidco-crystal can be characterized by any one, any two, any three, anyfour, any five, or any six or more of the peaks in FIG. 24 including,but not limited to, 5.36, 9.83, 15.80, 17.88, 18.70, 19.87, 21.21,21.85, and 25.96 degrees 2-theta (data as collected). The DSC showed amelting range of 143.3-145.2 degrees C. with a heat of fusion of 140.7J/g.

Example 15

R-(−)-Modafinil:Citric Acid Co-Crystal

R-(−)-modafinil:citric acid co-crystal was prepared by grindingR-(−)-modafinil (30.0 mg, 0.110 mmol, 82.2 percent R-isomer) with citricacid monohydrate (27.1 mg, 0.129 mmol). The powder was analyzed by PXRD(Bruker) and DSC, as shown in FIGS. 26 and 27, respectively. The PXRDpattern confirms that the co-crystal was made and shows manysimilarities to the PXRD pattern for the racemic modafinil:citric acidco-crystal. The R-(−)-modafinil:citric acid co-crystal can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 26 including, but not limited to, 5.18,7.23, 9.23, 12.32, 13.23, 17.25, 17.92, 18.76, 20.25, 21.30, and 23.71degrees 2-theta (data as collected). The DSC showed a melting range of83.5-89.0 degrees C. with a heat of fusion of 39.8 J/g.

Example 16

R-(−)-Modafinil:DL-Tartaric Acid Co-Crystal

The R-(−)-modafinil:DL-tartaric acid co-crystal was found from a highthroughput crystallization experiment from dichloromethane. The vialcontained a 1:2 mixture of R-(−)-modafinil (greater than 98 percentR-isomer) and DL-tartaric acid. The co-crystal was also found from a 1:1mixture of R-(−)-modafinil (greater than 98 percent R-isomer) andDL-tartaric acid in nitromethane. The solid materials were collected andcharacterized using PXRD (Bruker) and DSC, as shown in FIGS. 28 and 29,respectively. The R-(−)-modafinil:DL-tartaric acid co-crystal can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 28 including, but not limited to, 4.67,15.41, 17.97, 19.46, 20.50, 22.91, and 24.63 degrees 2-theta (ascollected). Endothermic transitions were present at about 107, 152, and187 degrees C.

Example 17

R-(−)-Modafinil:1-Hydroxy-2-Naphthoic Acid Co-Crystal

To a solid mixture of R-(−)-modafinil (98.6 mg; 0.361 mmol, greater than98 percent R-isomer) and 1-hydroxy-2-naphthoic acid (71.2 mg; 0.378mmol) was added o-xylene (4.5 mL). The mixture was heated to reflux forless than one minute at which point both solids dissolved. The solutionwas then slowly cooled to room temperature at which point a solidcrystallized. The solid was collected via filtration and air-dried. Thepowder was characterized using PXRD (Bruker), as shown in FIG. 30. Thesame material has been prepared from benzene, toluene, and acetone usingthe above procedure. The R-(−)-modafinil:1-hydroxy-2-naphthoic acidco-crystal can be characterized by any one, any two, any three, anyfour, any five, or any six or more of the peaks in FIG. 30 including,but not limited to, 5.27, 8.85, 10.60, 12.11, 14.47, 17.80, 18.80,21.20, 23.03, and 25.61 degrees 2-theta (as collected).

The R-(−)-modafinil:1-hydroxy-2-naphthoic co-crystal was also obtainedfrom a high throughput crystallization experiment from a vial containinga 1:1 mixture of R-(−)-modafinil (greater than 98 percent R-isomer) and1-hydroxy-2-naphthoic acid in nitromethane. The solid material wascollected and characterized using DSC and PXRD (Bruker), as shown inFIGS. 31 and 32, respectively. The R-(−)-modafinil:1-hydroxy-2-naphthoicacid co-crystal can be characterized by any one, any two, any three, anyfour, any five, or any six or more of the peaks in FIG. 32 including,but not limited to 5.34, 8.99, 10.68, 12.15; 14.51, 21.28, 23.14, and24.50 degrees 2-theta (as collected). DSC shows endothermic transitionsat about 118 and 179 degrees C.

Example 18

R-(−)-Modafinil:Orotic Acid Co-Crystal

The R-(−)-modafinil:orotic acid co-crystal was obtained from a highthroughput crystallization experiment from a vial containingR-(−)-modafinil (1 mg, 0.0036 mmol, greater than 98 percent R-isomer)and orotic acid (1.14 mg, 0.0073 mmol) in acetone (100 microliters). Thesolid material obtained was characterized using PXRD (Bruker) and DSC,as shown in FIGS. 33 and 34, respectively. The R-(−)-modafinil:oroticacid co-crystal can be characterized by any one, any two, any three, anyfour, any five, or any six or more of the peaks in FIG. 33 including,but not limited to, 9.77, 17.85, 20.52, 20.95, 24.03, and 26.80 degrees2-theta (as collected). PXRD peaks at 14.61 and 28.60 may correspond toexcess co-crystal former. Endothermic transitions were present at about116, 130, and 169 degrees C. TABLE IV Co-crystals of ModafinilCo-Crystal former Representative PXRD Peaks (degrees 2-theta) Malonicacid 5.00, 9.17, 10.08, 16.81, 18.26, 19.43, 21.36, 21.94, 22.77, 24.49,25.63, 26.37, 28.45 Glycolic acid 9.53, 14.93, 15.99, 19.05, 20.05,21.61, 22.77, 25.05 Maleic acid 4.69, 6.17, 9.63, 10.25, 15.67, 16.53,17.21, 18.05, 19.99, 21.85, 22.47 L-tartaric acid 6.10, 7.36, 9.38,14.33, 16.93, 17.98, 18.81, 20.15, 20.71, 22.49, 25.04 Citric acid 5.29,7.29, 9.31, 12.41, 13.29, 17.29, 17.97, 18.79, 21.37, 23.01 Succinicacid 5.45, 9.93, 15.87, 17.99, 18.75, 19.95, 21.95, 23.03, 25.07DL-tartaric acid 4.75, 9.53, 10.07, 15.83, 17.61, 19.37, 20.25, 21.53,22.55, 23.75 Fumaric acid (Form I) 5.45, 9.95, 10.91, 15.93, 18.03,18.81, 19.93, 20.25, 21.37, 21.95, 23.09, 25.01 Fumaric acid (Form II)6.47, 8.57, 9.99, 13.89, 14.53, 16.45, 17.13, 17.51, 18.39, 20.05,20.79, 25.93, 27.95 Gentisic acid 6.96, 12.92, 14.76, 17.40, 18.26,20.10, 20.94, 23.46, 24.36 Oxalic acid 5.98, 13.68, 14.80, 17.54, 19.68,21.12, 21.86, 28.90 1-hydroxy-2-naphthoic 5.72, 7.10, 11.48, 14.16,15.66, 17.92, 19.18, 20.26, 21.28, 21.94, 24.38, acid 26.86 *Malonicacid 5.04, 9.26, 16.73, 18.23, 19.37, 21.90, 22.74, 24.44, 25.67*Succinic acid 5.36, 9.83, 15.80, 17.88, 18.70, 19.87, 21.21, 21.85,25.96 *Citric acid 5.18, 7.23, 9.23, 12.32, 13.23, 17.25, 17.92, 18.76,20.25, 21.30, 23.71 **DL-tartaric acid 4.67, 15.41, 17.97, 19.46, 20.50,22.91, 24.63 **1-hydroxy-2- 5.27, 8.88, 10.60, 12.11, 14.47, 17.80,18.80, 21.20, 23.03, 25.61 naphthoic acid **Orotic acid 9.77, 17.85,20.52, 20.95, 24.03, 26.80 **Gentisic acid 7.07, 7.51, 9.07, 12.31,16.03, 17.63, 18.39, 19.83, 21.27, 23.57, 26.93, 28.85*= API is R-(−)-modafinil with 82.2 percent (purity) R-(−)-modafinil(17.8 percent S-(+)-modafinil)**= API is R-(−)-modafinil with greater than 98 percent (purity)R-(−)-modafinil (less than 2 percent S-(+).modafinilAll other co-crystals comprise racemic modafinil

Example 19

Acetic Acid Solvate of Racemic Modafinil

To racemic modafinil (12.9 mg, 0.047 mmol) was added acetic acid (40microliters). The mixture was heated at 50 degrees C. to completelydissolve the solid. The solution was allowed to cool to roomtemperature, and left overnight, which yielded no precipitation. Thesolution was then evaporated under flowing nitrogen until precipitationwas observed. The resulting solid was further dried under flowingnitrogen. Characterization of the product has been achieved via PXRD(Rigaku), TGA, DSC, and Raman spectroscopy, as shown in FIGS. 35-38,respectively. An alternative method for the preparation of the aceticacid solvate of modafinil was also completed. A sample of modafinilacetic acid solvate was prepared by dissolving racemic modafinil (12.9mg, 0.047 mmol) in acetic acid (40 microliters) and incubating at 65degrees C. for 30 minutes to dissolve, then cooling to 25 degrees C. toincubate overnight. The sample was then evaporated to approximately ⅓volume. After centrifugation of the sample, rapid nucleation and growthof crystals was observed. An additional 20 microliters of acetic acidwas then added. The sample was heated at 50 degrees C. until partialdissolution of the crystals was observed. The sample was then cooled toroom temperature over a 1 hour period, then to 5 degrees C. for 3 hoursin an attempt to induce crystal growth. The sample was then dried undernitrogen gas. Rapid appearance of crystals was observed. The modafinilacetic acid solvate can be characterized by any one, any two, any three,any four, any five, or any six or more of the peaks in FIG. 35including, but not limited to, 6.17, 9.63, 15.69, 17.97, 19.99, and21.83 degrees 2-theta (data as collected).

Example 20

Tetrahydrofuran Solvate of Racemic Modafinil

The tetrahydrofuran (THF) solvate of modafinil was prepared by placingracemic modafinil (10.4 mg, 0.038 mmol) in tetrahydrofuran (1 mL). Thepowder did not completely dissolve in THF and converted overnight intolong, fine, needle shaped crystals which were collected and analyzed byPXRD (Rigaku), as shown in FIG. 39. The modafinil tetrahydrofuransolvate can be characterized by any one, any two, any three, any four,any five or any six or more of the peaks in FIG. 39 including, but notlimited to, 6.97, 9.79, 10.97, 16.19, 19.03, 19.71, 20.59, 22.25, and25.13 degrees 2-theta (data as collected).

Example 21

1,4-Dioxane Solvate of Racemic Modafinil

To racemic modafinil (11.6 mg, 0.042 mmol) was added 1,4-dioxane (1 mL).The mixture was then left overnight and converted to long, fine, needleshaped crystals which were collected and analyzed by PXRD (Rigaku), asshown in FIG. 40. The modafinil 1,4-dioxane solvate can be characterizedby any one, any two, any three, any four, any five, or any six or moreof the peaks in FIG. 40 including, but not limited to, 6.93, 9.85,10.97, 16.19, 18.97, 19.61, 20.33, 20.65, and 22.07 degrees 2-theta(data as collected). PXRD pattern also contains several spikes whichwere a result of instrument error and could not be removed.

Example 22

Methanol Solvate of Racemic Modafinil

The methanol solvate of modafinil is obtained by evaporating 2 mL of a30 mg/mL racemic modafinil solution in methanol under flowing nitrogenovernight. The methanol solvate was characterized by PXRD (Rigaku), TGA,and DSC, as shown in FIGS. 41, 42, and 43, respectively. The modafinilmethanol solvate can be characterized by any one, any two, any three,any four, any five, or any six or more of the peaks in FIG. 41including, but not limited to, 6.15, 9.89, 12.25, 15.69, 17.97, 20.07,21.85, and 22.73 degrees 2-theta (data as collected).

Example 23

Nitromethane Solvate of Racemic Modafinil To racemic modafinil (12.9 mg,0.047 mmol) was added nitromethane (1 mL). The mixture which did notfully dissolve was left overnight and converted to large rectangularcrystals. The solid was collected and analyzed by PXRD (Rigaku), asshown in FIG. 44. The modafinil nitromethane solvate can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 44 including, but not limited to, 6.17,9.77, 15.89, 18.11, 20.07, 22.17, 22.91, 25.31, and 25.83 degrees2-theta (data as collected).

Example 24

Acetone Solvate of Racemic Modafinil

A solution containing racemic modafinil (300 mg, 0.001 mol) and glutaricacid (150 mg, 0.001 mol) in acetone (3 mL) was heated until it wasboiling in order to dissolve all solid material. Once the solidsdissolved, the solution was placed on an aluminum block at 5 degrees C.After 15 minutes of sitting at 5 degrees C., crystals began to form atthe bottom of the vial. The solution was then decanted and the singlecrystals were collected and analyzed using PXRD (Rigaku), as shown inFIG. 45. The crystals were determined to be an acetone solvate ofmodafinil. The acetone solvate of modafinil can be characterized by anyone, any two, any three, any four, any five, or any six or more of thepeaks in FIG. 45 including, but not limited to, 6.11, 9.53, 15.81,18.11, 20.03, 21.63, 22.45, 25.23, 25.65, 28.85, 30.23, and 32.93degrees 2-theta (as collected). The acetone solvate may also be obtainedfollowing the procedure above with several other co-crystal formersincluding adipic acid, lactobionic acid, maleic acid, and glycolic acid.

Example 25

Racemic modafinil (1 mg, 0.0037 mmol) and mandelic acid (0.55 mg, 0.0037mmol) were dissolved in acetone (400 microliters). The solution wasallowed to evaporate to dryness and the resulting solid wascharacterized using PXRD (Rigaku), as shown in FIG. 46. The obtainedsolid is a mixture of the acetone solvate and another product ofmodafinil. The form can be characterized by any one, any two, any three,any four, any five, or any six or more of the peaks in FIG. 46including, but not limited to, 6.11, 9.53, 15.77, 18.03, 20.01, and21.61 degrees 2-theta (background removed). Other peaks including 6.75,10.31, 14.77, and 23.27 may correspond to a modafinil polymorph.

Example 26

Racemic modafinil (1 mg, 0.0037 mmol) and fumaric acid (0.42 mg, 0.0037mmol) were dissolved in 1,2-dichloroethane (400 microliters). Thesolution was allowed to evaporate to dryness and the resulting solid wascharacterized using PXRD (Rigaku), as shown in FIG. 47. The obtainedsolid may be a solvate of modafinil. The form can be characterized byany one, any two, any three, any four, any five, or any six or more ofthe peaks in FIG. 47 including, but not limited to, 5.87, 8.95, 12.49,13.99, 18.19, 19.99, 21.57, and 25.01 degrees 2-theta (backgroundremoved).

Example 27

Novel Form of Racemic Modafinil

Racemic modafinil was dispensed from a stock solution containing 50 mgof modafinil in 20 mL of a 15:5 acetone/methanol mixture. The solutionwas then evaporated to dryness under a flow of nitrogen. Benzoic acidwas dispensed from an acetone solution and the mixture was againevaporated to dryness. 200 microliters of isopropyl alcohol or methanolwas then added and the vials were capped. After standing at roomtemperature for one day, the caps were removed and the solvent wasallowed to evaporate. PXRD (Rigaku) was carried out on the sample, asshown in FIG. 48. The novel form of racemic modafinil, which may be apolymorph or a co-crystal, is denoted as form VII. Form VII can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 48 including, but not limited to, 5.47,9.99, 15.73, 17.85, 18.77, 20.05, 21.23, 22.05, 23.15, and 25.13 degrees2-theta (data as collected).

Example 28

Racemic Modafinil:Malonic Acid Co-Crystal Pharmacokinetic Study in Dogs

The racemic modafinil:malonic acid co-crystal (from Example 1) wasadministered to dogs in a pharmacokinetic study. Particles ofmodafinil:malonic acid co-crystal with a median particle size of about16 micrometers were administered in the study. As a reference,micronized modafinil with a median particle size of about 2 micrometerswas also administered in the study. The AUC of the modafinil:malonicacid co-crystal was determined to be 40 to 60 percent higher than thatof the pure modafinil. Such a higher bioavailability illustrates themodulation of an important pharmacokinetic parameter due to anembodiment of the present invention. A compilation of importantpharmacokinetic parameters measured during the animal study are includedin Table V. TABLE V Pharmacokinetic parameters of modafinil:malonic acidco-crystal and pure modafinil in dogs Parameter Pure ModafinilModafinil:malonic acid co-crystal Median particle size 2 micrometers 16micrometers C_(max) (ng/mL) 11.0 ± 5.9  10.3 ± 3.4  T_(max) (hours) 1.3± 0.6 1.7 ± 0.6 AUC (relative) 1.0 1.4-1.6 Half-life (hours) 2.1 ± 0.75.1 ± 2.4

Example 29

Racemic Modafinil:Malonic Acid Co-Crystal Solid-State Stability

The stability of the racemic modafinil:malonic acid co-crystal wasmeasured at various temperatures and relative humidities over a fourweek period. No degradation was found to occur at 20 or 40 degrees C. At60 degrees C., about 0.14 percent degradation per day was determinedbased on a simple exponential model. At 80 degrees C., about 8 percentdegradation per day was determined.

The stability of the modafinil:malonic acid co-crystal was also measuredat various temperatures and relative humidities over a 26 week period.FIGS. 49 and 50 show the % area impurities as measured via HPLC versustime (weeks) for samples stored at various conditions including: 25degrees C., 60% RH; 40 degrees C., 75 percent RH; 40 degrees C., ambientRH; 60 degrees C., ambient RH; 80 degrees C., ambient RH; and −20degrees C. These data show that the compound is stable when stored at orbelow 40 degrees C. for at least 26 weeks. FIG. 51 compares PXRDpatterns of initial and 26 week old samples of the modafinil:malonicacid co-crystal for several temperatures and RH levels.

Example 30

Formulation of Racemic Modafinil:Malonic Acid Co-Crystal

The formulation of a racemic modafinil:malonic acid co-crystal wascompleted using lactose. Two mixtures, one of modafinil and lactose, andthe second of modafinil:malonic acid co-crystal and lactose, were groundtogether in a mortar an pestle. The mixtures targeted a 1:1 weight ratioof modafinil to lactose. In the modafinil and lactose mixture, 901.2 mgof modafinil and 901.6 mg of lactose were ground together. In themodafinil:malonic acid co-crystal and lactose mixture, 1221.6 mg ofco-crystal and 871.4 mg of lactose were ground together. The resultingpowders were analyzed by PXRD and DSC. The PXRD patterns and DSCthermograms of the mixtures showed virtually no change upon comparisonwith both individual components. The DSC of the co-crystal mixtureshowed only the co-crystal melting peak at 113.6 degrees C. with a heatof fusion of 75.9 J/g. This heat of fusion is 59.5% of that found forthe co-crystal alone (127.5 J/g). This result is consistent with a 58.4%weight ratio of co-crystal in the mixture. The DSC of the modafinil andlactose mixture had a melting point of 165.7 degrees C. This is slightlylower then the measured melting point of modafinil (168.7 degrees C.).The heat of fusion of the mixture (59.3 J/g) is 46.9% that of themodafinil alone (126.6 J/g), which is consistent with the estimatedvalue of 50%.

The in vitro dissolution of both the modafinil:malonic acid co-crystaland pure modafinil were tested in capsules. Both gelatin andhydroxypropylmethyl cellulose (HPMC) capsules were used in thedissolution study. The capsules were formulated with and withoutlactose. All formulations were ground in a mortar and pestle prior totransfer into a capsule. The dissolution of the capsules was tested in0.01 M HCl (See FIG. 52).

In 0.01N HCl, Using Sieved and Ground Materials in Gelatin Capsules:

Modafinil and the modafinil:malonic acid co-crystal were passed througha 38 micrometer sieve. Gelatin capsules (Size 0, B&B Pharmaceuticals,Lot # 15-01202) were filled with 200.0 mg sieved modafinil, 280.4 mgsieved modafinil:malonic acid co-crystal, 200.2 mg ground modafinil, or280.3 mg ground modafinil:malonic acid co-crystal. Dissolution studieswere performed in a Vankel VK 7000 Benchsaver Dissolution TestingApparatus with the VK750D heater/circulator set at 37 degrees C. At 0minutes, the capsules were dropped into vessels containing 900 mL 0.01 MHCl and stirred by paddles.

Absorbance readings were taken using a Cary 50 Spectrophotometer(wavelength set at 260 nm) at the following time points: 0, 5, 10, 15,20, 25, 30, 40, 50, and 60 minutes. The absorbance values were comparedto those of standards and the modafinil concentrations of the solutionswere calculated.

In 0.01N HCl, Using Ground Materials in Gelatin or HPMC Capsules, withand without Lactose:

Modafinil and the modafinil:malonic acid co-crystal were mixed withequivalent amounts of lactose (Spectrum, Lot QV0460) for approximately 5minutes. Gelatin capsules (Size 0, B&B Pharmaceuticals, Lot # 15-01202)were filled with 400.2 mg modafinil and lactose (approximately 200 mgmodafinil), or 561.0 mg modafinil:malonic acid co-crystal and lactose(approximately 200 mg modafinil). HPMC capsules (Size O, Shionogi, Lot #A312A6) were filled with 399.9 mg modafinil and lactose, 560.9 mgmodafinil:malonic acid co-crystal and lactose, 199.9 mg modafinil, or280.5 mg modafinil:malonic acid co-crystal. The dissolution study wascarried out as described above.

Example 31

In Vitro Dissolution

FIG. 53 shows in vitro dissolution data of micronized racemicmodafinil:malonic acid co-crystal and of micronized modafinil insimulated gastric fluid (SGF) and in simulated intestinal fluid (SIF).Both samples were blended with lactose and filled into HPMC capsules.The co-crystal releases modafinil into solution more quickly in both SGFand SIF than does the free form of modafinil. FIG. 54 compares thedissolution of an HPMC capsule filled with the modafinil:malonic acidco-crystal blended with lactose and that of a PROVIGIL tablet. FIG. 55shows a dynamic vapor sorption (IVS) isotherm plot of themodafinil:malonic acid co-crystal. This plot shows no appreciable wateradsorption up to at least 40 percent RH at 26 degrees C.

Example 32

In Vivo Studies

A pharmacokinetic study was completed with dogs using both racemicmodafinil:malonic acid formulated with lactose and PROVIGIL tablets (200mg). Seven capsules were filled with the modafinil:malonic acidco-crystal and lactose to 476.24+/−2 mg, each containing 200 mgmodafinil. FIG. 56 shows the co-crystal formulation has an increasedC_(max) and an increased bioavailability. Severel importantpharmacokinetic parameters are described in Table VI. In Table VI,“C_(max)” is the maximum blood plasma concentration, “AUC (inf)” is theextrapolated area under the curve, “t_(1/2)” is the amount of time forthe blood plasma level to decrease to half of the C_(max) levelbeginning at administration, “T_(max)” is the time to maximum bloodplasma concentration from administration, “CL” is the clearance rate ofmodafinil, and “F %” is the percent bioavailability. TABLE VI PKparameters of modafinil: malonic acid co-crystal and PROVIGIL from InVivo study Cmax AUC (inf) t_(1/2) Tmax CL F % PROVIGIL (200 mg) Mean7838.33 41193.33 1.76 2.00 524.17 66.48 SD 2734.35 8104.32 0.88 0.63146.98 13.08 % CV 34.9 19.7 49.7 31.6 28.0 19.7 Modafinil: malonic acid(200 mg modafinil) Mean 11246.67 50545.00 1.63 2.00 368.33 81.57 SD1662.13 10635.46 0.64 0.89 165.60 17.16 % CV 14.8 21.0 39.5 44.7 45.021.0

Example 33

R-(−)-Modafinil:Gentisic Acid Co-Crystal

R-(−)-modafinil (50 mg, 0.183 mmol, greater than 98 percent R-isomer)and gentisic acid (28.2 mg, 0.183 mmol) were placed in a stainless steelvial. 10 microliters of acetone was added to the vial. The vial was thenplaced in a grinder (wig-1-bug, Bratt Technologies, 115V/60 Hz) and thesolid mixture was milled for 5 minutes. The resultant powder was thencollected and characterized using PXRD (Rigaku), as shown in FIG. 57.The R-(−)-modafinil:gentisic acid co-crystal can be characterized by anyone, any two, any three, any four, any five, or any six or more of thepeaks in FIG. 57 including, but not limited to, 7.07, 9.07, 12.31,13.03, 14.09, 18.93, 19.83, and 21.27 degrees 2-theta (as collected).Other PXRD peaks at 7.51, 16.03, 17.63, 18.39, 23.57, 26.93, and 28.85degrees 2-theta correspond to excess co-crystal former.

Example 34

Channel Solvates of Racemic Modafinil

Channel solvates of modafinil have been unexpectedly discovered. Thechannel solvate was made from a solution of racemic modafinil (97.9 mg,0.358 mmol) and 1-hydroxy-2-napthoic acid (68.8 mg, 0.366 mmol) inacetone (3.15 mL), dissolved over a 60 degrees C. hotplate. The solutionwas then evaporated under flowing nitrogen while hot to 1.6 mL totalvolume. Once cooled, the solution was seeded with ground racemicmodafinil:1-hydroxy-2-naphtoic acid co-crystal. Single crystals wereobtained and characterized using single x-ray analysis. Single-crystalx-ray parameters: P2(1)/n, a=12.737(3) angstroms, b=5.5945(11)angstroms, c=22.392(5) angstroms, alpha=90 degrees, beta=104.140(4)degrees, gamma=90 degrees, V=1547.3(5) cubic angstroms, Z=2. FIGS. 58and 59 show packing diagrams of the acetone channel solvate ofmodafinil. The packing diagrams show acetone with a variable positionwithin the channel structure. An ethyl acetate channel solvate has alsobeen prepared according to the method above using ethyl acetate in placeof acetone.

Example 35

o-Xylene Hemisolvate of Racemic Modafinil

An o-xylene hemisolvate was formed by preparing a 1:2 solution ofracemic modafinil (49.6 mg, 0.181 mmol) and 1-hydroxy-2-napthoic acid(68.3 mg, 0.363 mmol) in o-xylene (4.5 mL). The mixture was heated on ahotplate with swirling until all solids were dissolved. The solution wasthen left to crystallize in a sealed vial. The resulting powder wascollected in a centrifuge filter and analyzed by PXRD (Bruker), as shownin FIG. 60. Raman spectroscopy (FIG. 61), TGA (FIG. 62), and DSC (FIG.63) were also used to analyze and characterize the hemisolvate. Theo-xylene solvate can be characterized by any one, any two, any three,any four, any five, or any six or more of the peaks in FIG. 60including, but not limited to, 5.31, 6.53, 6.96, 10.68, 14.20, 17.64,19.93, 25.69, and 26.79 degrees 2-theta. The o-xylene solvate can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 61 (middle spectrum) including, but notlimited to, 1641, 1407, 1379, 1211, 1024, and 721 cm⁻¹.

Example 36

Benzene Hemisolvate of Racemic Modafinil

A benzene hemisolvate was formed by preparing a 1:2 solution of racemicmodafinil (50.6 mg, 0.181 mmol) and 1-hydroxy-2-napthoic acid (70.1 mg,0.373 mmol) in benzene (1.8 mL). The mixture was heated on a hotplatewith swirling until all solids were dissolved. The solution was thenleft to crystallize in a sealed vial. The resulting powder was collectedin a centrifuge filter and analyzed by PXRD (Bruker), as shown in FIG.64. Raman spectroscopy (FIG. 65), TGA (FIG. 66), and DSC (FIG. 67) werealso used to analyze and characterize the hemisolvate. The benzenesolvate can be characterized by any one, any two, any three, any four,any five, or any six or more of the peaks in FIG. 64 including, but notlimited to, 5.82, 6.09, 8.11, 10.28, 12.06, 13.28, 14.73, 17.03, 19.11,19.93, 21.23, 25.38, and 26.43 degrees 2-theta. The benzene solvate canbe characterized by any one, any two, any three, any four, any five, orany six or more of the peaks in FIG. 65 (middle spectrum) including, butnot limited to, 1637, 1600, 1409, 1380, 1214, 1025, 998, and 721 cm⁻¹.

Example 37

Toluene Hemisolvate of Racemic Modafinil

A toluene hemisolvate was formed by making a 1:2 solution of racemicmodafinil (37.3 mg, 0.136 mmol) and 1-hydroxy-2-napthoic acid (51.3 mg,0.273 mmol) in toluene (1 mL). The mixture was heated on a hotplate withswirling until all solids were dissolved. The solution was then left tocrystallize in a sealed vial. The resulting powder was collected in acentrifuge filter and analyzed by PXRD (Bruker), as shown in FIG. 68.Raman spectroscopy (FIG. 69), TGA (FIG. 70), and DSC (FIG. 71) were alsoused to analyze and characterize the hemisolvate. The toluene solvatecan be characterized by any one, any two, any three, any four, any five,or any six or more of the peaks in FIG. 68 including, but not limitedto, 5.30, 5.96, 10.65, 12.90, 14.51, 17.60, and 18.15 degrees 2-theta.The toluene solvate can be characterized by any one, any two, any three,any four, any five, or any six or more of the peaks in FIG. 69 (middlespectrum) including, but not limited to, 1640, 1581, 1408, 1380, 1209,1024, 1001, and 722 cm⁻¹.

Example 38

Pharmacokinetics of Isomers of Modafinil

A dog pharmacokinetic study (N=6) of a single intravenous dose ofR-(−)-modafinil was completed. The purity of the R-(−)-modafinil in theadministered formulation was ca 80 percent. This formulation wascompared to a formulation of racemic modafinil, also administered by theintravenous route to the same dogs in a crossover design. Results arereported in Table VII. Ir. Table VII, “C_(max)” is the maximum bloodplasma concentration, “AUC (inf)” is the extrapolated area under thecurve, “t_(1/2)” is the amount of time for the blood plasma level todecrease to half of the C_(max) level beginning at administration,“V_(d)” is the volume of distribution, and “CL” is the clearance rate ofmodafinil. TABLE VII PK parameters of racemic modafinil andR-(−)-modafinil from In Vivo study C_(max) AUC (inf) t_(1/2) V_(d) CL(ng/mL) (ng/mL × hr) (hr) (mL/kg) (mL/hr × kg) Racemic Modafinil (5mg/kg IV) Mean 8682.83 15117.50 1.05 588.83 341.00 SD 1413.71 2870.240.16 96.41 65.63 % CV 16.3 19.0 15.4 16.4 19.2 R-(−)-modafinil (5 mg/kgIV) Mean 7806.67 15905.17 1.53 646.67 340.33 SD 827.97 4958.47 1.1168.10 102.39 % CV 10.6 31.2 72.5 10.5 30.1These results suggest that there is no significant difference betweenthe pharmacokinetics of R-(−)-modafinil and racemic modafinil followingintravenous administration.

These results are in contrast to the pharmacokinetics of the isomerswhen administered by the oral route (See U.S. Pat. No. 4,927,855, whichis herein incorporated by reference in its entirety). In said study,four dogs were administered 30 mg/kg oral dose of either R-(−)-modafinil(40-982), S-(+)-modafinil (40-983), or racemic modafinil (40-476). TheAUC values were calculated from plasma concentration of both forms(40476) and the sulfone metabolite measured from 2 to 9 hours post-doseadministration. Table VIII shows the pharmacokinetic data. TABLE VIII PKparameters of racemic modafinil, R-(−)-modafinil, and S-(+)-modafinilfrom In Vivo study Compound administered Mean AUC (racemate) Mean AUC(sulfone) (30 mg/kg) (mg/L × hr) (mg/L × hr) 40-476 (racemate) 46.76 +/−6.95  35.12 +/− 6.93  40-982 (R-(−)-modafinil) 97.22 +/− 12.58 8.69 +/−1.22 40-983 (S-(+)-modafinil) 50.94 +/− 8.77  83.12 +/− 21.66These results suggest striking differences in the metabolism of bothisomers of modafinil, leading to differences in the formation of theinactive sulfone metabolite therefore resulting in higher exposure tothe API when administered as R-(−)-modafinil. The different profileobserved between the intravenous and the oral route could be explainedby the fact that the formation of the sulfone metabolite is primarilycatalyzed by cytochrome CYP3A4 which is both present at the intestinaland hepatic level, and that the affinity of CYP3A4 to S-(+)-modafinil ishigher (stereoselective metabolism) than that to R-(−)-modafinil. Thiscan result in faster metabolite formation with S-(+)-modafinil which canreduce the exposure to the API.

Example 39

R-(−)-Modafinil Ethanol Solvate

A solution containing R-(−)-modafinil (100 mg, 0.366 mmol, 85.4 percentR-isomer) and racemic modafinil (40 mg, 0.146 mmol) in ethanol (3 mL)was prepared. The mixture was heated to reflux in order to dissolve theentire solid and was then cooled to room temperature (25 degrees C.).After remaining at room temperature for 15 minutes, the solution wasplaced at 5 degrees C. overnight. A solid precipitate was observed after1 day and was collected, dried, and characterized using PXRD and TGAFIGS. 72 and 73). The solid was determined to be an ethanol solvate ofR-(−)-modafinil.

R-(−)-modafinil ethanol solvate can be characterized by any one, anytwo, any three, any four, any five, or any six or more of the peaks inFIG. 72 including, but not limited to, 6.13, 9.59, 15.69, 17.97, 20.05,21.55, 22.35, 25.77, and 29.07 degrees 2-theta (Rigaku PXRD, data ascollected).

TGA of the R-(−)-modafinil ethanol solvate characterized in FIG. 73showed about a 5.4 percent weight loss between about 25 and about 140degrees C.

Example 40

R-(−)-Modafinil Benzyl Alcohol Solvate

R-(−)-modafinil (100 mg, 0.366 mmol) was milled with benzyl alcohol (40microliters) for 5 minutes. The milled powder was then analyzed by PXRD,DSC, and TGA (FIGS. 74, 75, and 76). The powder was determined to be abenzyl alcohol solvate of R-(−)-modafinil.

R-(−)-modafinil benzyl alcohol solvate can be characterized by any one,any two, any three, any four, any five, or any six or more of the peaksin FIG. 74 including, but not limited to, 5.77, 7.76, 10.48, 15.78,17.80, 18.57, 21.53, 22.97, and 27.73 degrees 2-theta (Bruker PXRD, dataas collected).

DSC of the R-(−)-modafinil benzyl alcohol solvate characterized in FIG.75 showed an endothermic transition at about 83 degrees C.

TGA of the R-(−)-modafinil benzyl alcohol solvate characterized in FIG.76 showed about a 28.5 percent weight loss between about 25 and about125 degrees C.

Example 41

R-(−)-Modafinil Isopropanol Solvate

R-(−)-modafinil was slurried overnight in isopropanol. The liquid wasfiltered out in a centrifuge filter, then dried under flowing nitrogengas at 5 degrees C. The resulting solid was analyzed via PXRD.

R-(−)-modafinil isopropanol solvate can be characterized by any one, anytwo, any three, any four, any five, or any six or more of the peaks inFIG. 77 including, but not limited to, 5.76, 7.77, 10.49, 15.79, 18.58,21.53, 25.76, and 27.74 degrees 2-theta (Bruker PXRD, data ascollected).

Example 42

R-(−)-Modafinil Acetonitrile Solvate

100 mg of R-(−)-modafinil was slurrie in acetonitrile for 2 days. Thesolid was filtered from the suspension and analyzed by PXRD.

R-(−)-modafinil acetonitrile solvate can be characterized by any one,any two, any three, any four, any five, or any six or more of the peaksin FIG. 78 including, but not limited to, 5.29, 6.17, 8.16, 10.19,11.19, and 21.86 degrees 2-theta (Bruker PXRD, data as collected).

Example 43

R-(−)-Modafinil:Glutaric Acid Co-Crystal

R-(−)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) andglutaric acid (15-20 mg) were ground together in the presence of onedrop of benzyl alcohol.

The resultant solid was characterized by PXRD (See FIG. 79) and maycomprise a co-crystal. The R-(−)-modafinil:glutaric acid co-crystal canbe characterized by any one, any two, any three, any four, any five, orany six or more of the peaks in FIG. 79 including, but not limited to,4.30, 8.67, 9.78, 17.99, 18.92, 19.74, 20.50, 21.36, 22.25, 23.87,27.16, 29.24, and 32.46 degrees 2-theta (Bruker PXRD, data ascollected).

Wet grinding was also used with acetone and with water, both of whichresulted in the formation of the co-crystal.

Example 44

R-(−)-Modafinil:Citric Acid Co-Crystal

R-(−)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) andcitric acid monohydrate (15-20 mg) were ground together in the presenceof one drop of benzyl alcohol.

The resultant solid was characterized by PXRD (See FIG. 80) and maycomprise a co-crystal. The R-(−)-modafinil:citric acid co-crystal can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 80 including, but not limited to, 5.23,7.06, 9.10, 12.43, 13.18, 14.37, 17.34, 17.95, 20.85, 21.39, 22.03,22.96, 23.54, and 24.93 degrees 2-theta (Bruker PXRD, data ascollected).

Wet grinding was also used with acetone which resulted in the formationof the co-crystal.

Example 45

R-(−)-Modafinil:L-Tartaric Acid Co-Crystal

R-(−)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) andL-tartaric acid (15-20 mg) were ground together in the presence of onedrop of benzyl alcohol.

The resultant solid was characterized by PXRD (See FIG. 81) and maycomprise a co-crystal. The R-(−)-modafinil:L-tartaric acid co-crystalcan be characterized by any one, any two, any three, any four, any five,or any six or more of the peaks in FIG. 81 including, but not limitedto, 4.56, 10.33, 14.45, 17.29, 19.91, 21.13, 23.10, 24.10, and 26.76degrees 2-theta (Bruker PXRD, data as collected).

Wet grinding was also used with acetone and with water, both of whichresulted in the formation of the co-crystal.

Example 46

R-(−)-Modafinil:Oxalic Acid Co-Crystal

R-(−)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) andoxalic acid (15-20 mg) were ground together in the presence of one dropof benzyl alcohol.

The resultant solid was characterized by PXRD (See FIGS. 82A and 82B)and may comprise one or more co-crystals. The R-(−)-modafinil:oxalicacid (Form I) co-crystal can be characterized by any one, any two, anythree, any four, any five, or any six or more of the peaks in FIG. 82Aincluding, but not limited to, 5.99, 14.73, 16.59, 17.38, 18.64, 25.66,and 28.85 degrees 2-theta (Bruker PXRD, data as collected). TheR-(−)-modafinil:oxalic acid (Form ED co-crystal can be characterized byany one, any two, any three, any four, any five, or any six or more ofthe peaks in FIG. 82B including, but not limited to, 5.66, 14.76, 17.20,17.63, 19.60, 24.90, and 28.84 degrees 2-theta (Bruker PXRD, data ascollected).

Wet grinding was also used with acetone and with water, both of whichresulted in the formation of the co-crystal.

Example 47

R-(−)-Modafinil:Palmitic Acid Co-Crystal

R-(−)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) andpalmitic acid (15-20 mg) were ground together in the presence of onedrop of benzyl alcohol.

The resultant solid was characterized by PXRD (See FIG. 83) and maycomprise a co-crystal. The R-(−)-modafinil:palmitic acid co-crystal canbe characterized by any one, any two, any three, any four, any five, orany six or more of the peaks in FIG. 83 including, but not limited to,3.80, 6.55, 7.66, 10.24, 11.49, 19.48, 21.09, 21.74, 22.20, 22.97, and23.99 degrees 2-theta (Bruker PXRD, data as collected).

Example 48

R-(−)-Modafinil:L-Proline Co-Crystal

R-(−)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) andL-proline (15-20 mg) were ground together in the presence of one drop ofbenzyl alcohol.

The resultant solid was characterized by PXRD (See FIG. 84) and maycomprise a co-crystal. The R-(−)-modafinil:L-proline co-crystal can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 84 including, but not limited to, 6.52,8.53, 10.25, 14.69, 19.06, 19.71, 20.75, 22.29, 22.75, 25.08, and 26.27degrees 2-theta (Bruker PXRD, data as collected).

Wet grinding was also used with acetone and with methanol, both of whichresulted in the formation of the co-crystal.

Example 49

R-(−)-Modafinil:Salicylic Acid Co-Crystal

R-(−)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) andsalicylic acid (15-20 mg) were ground together in the presence of onedrop of benzyl alcohol.

The resultant solid was characterized by PXRD (See FIG. 85) and maycomprise a co-crystal. The R-(−)-modafinil:salicylic acid co-crystal canbe characterized by any one, any two, any three, any four, any five, orany six or more of the peaks in FIG. 85 including, but not limited to,8.92, 10.85, 12.18, 14.04, 17.07, 17.59, 18.81, 21.24, 23.32, 25.22, and28.59 degrees 2-theta (Bruker PXRD, data as collected).

Example 50

R-(−)-Modafinil:Lauric Acid Co-Crystal

R-(−)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) andlauric acid (15-20 mg) were ground together in the presence of one dropof benzyl alcohol.

The resultant solid was characterized by PXRD (See FIG. 86) and maycomprise a co-crystal. The R-(−)-modafinil:lauric acid co-crystal can becharacterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 86 including, but not limited to, 3.12,6.55, 10.24, 13.97, 16.40, 17.62, 19.02, 20.05, 21.38, 22.24, 23.81, and25.96 degrees 2-theta (Bruker PXRD, data as collected).

Wet grinding was also used with acetone and with methanol, both of whichresulted in the formation of the co-crystal.

Example 51

R-(−)-Modafinil:L-Malic Acid Co-Crystal

R-(−)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) andL-malic acid (15-20 mg) were ground together in the presence of one dropof acetone.

The resultant solid was characterized by PXRD (See FIG. 87) and maycomprise a co-crystal. The R-(−)-modafinil:L-malic acid co-crystal canbe characterized by any one, any two, any three, any four, any five, orany six or more of the peaks in FIG. 87 including, but not limited to,4.62, 9.32, 10.32, 15.83, 16.71, 17.38, 19.30, 19.93, 21.48, 23.07,24.26, and 27.25 degrees 2-theta (Bruker PXRD, data as collected).

Example 52

Preparation of benzhdrylthioacetic Acid from Benzhydrol

To a solution of benzhydrol (100 g, 0.542 mol) in trifluoroacetic acid(300 mL) at room temperature (about 22 degrees C.) was addedthioglycolic acid (50 g, 0.542 mol) drop wise over 20 minutes. Reactionprogress was monitored by thin layer chromatography (TLC). The reactionwas complete within one hour at which point water (1000 mL) was addedslowly into the reaction mixture causing the product to precipitate. Theresulting precipitate was filtered, washed with water and driedovernight under high vacuum to give benzhydrylthioacetic acid (139.3 g,99.3%) as a pale yellow solid. (See Prisinzano, T. et al, TetrahedronAsymm., 2004, 15, 1053-1058)

Example 53

Preparation of Benzhdrylthioacetic Acid from Bromodiphenylmethane (OnePot Procedure)

To a solution of thiourea (30.4 g, 0.399 mol) in water (200 mL) wasadded bromodiphenylmethane (98.8 g, 0.399 mol) at 42 degrees C. Themixture was heated gradually to reflux for 10 minutes. The reactionmixture was then cooled to 50 degrees C. and 5 N NaOH (200 mL) wassubsequently added. The reaction mixture was then heated to reflux(101-102° C.) for 30 minutes and subsequently cooled to 60 degrees C. Tothis reaction mixture was slowly added a solution of chloroacetic acid(53.4 g, 0.565 mol) and NaOH (22.2 g) in water (150 mL) over 45 minutes.The reaction mixture was stirred for another 30 minutes. The reactionwas then cooled to room temperature and washed with t-butylmethylether(200 ml) to remove any non carboxylic acid impurities. The aqueous layerwas acidified (pH 2.0) using concentrated HCl (50 mL). The resultingprecipitate was filtered, washed with water (2×200 mL) and heptane (200mL) and allowed to air dry to give benzhydrylthioacetic acid (116.8 g,100%) as a colorless solid. (See U.S. Pat. No. 4,066,686)

Example 54

Preparation of Benzhdrylthioacetic Acid from Benzhydrol UsingTrifluoroacetic Acid in Dichloromethane

To a solution of benzhydrol (90 g, 0.488 mol) and trifluoroacetic acid(90 mL) in dichloromethane (300 mL) was added thioglycolic acid (40 g,0.488 mol) in dichloromethane (60 mL) drop wise over 20 minutes. Thereaction was completed in one hour. The solvent was removed in vacuo togive a crude solid, which was dried overnight under high vacuum. Thesolid was treated with 2 N NaOH (1.0 L) and washed witht-butylmethylether (200 ml) to remove non carboxylic acid impurities.The aqueous solution was then acidified with concentrated HCl and theresulting precipitate was collected, washed with water and dried to givebenzhydrylthioacetic acid (128.5 g) as a colorless solid.

Example 55

Preparation of benzhydrylsulfinylacetic Acid from BenzhdrylthioaceticAcid

To a suspension of benzhydrylthioacetic acid (63.7 g, 0.246 mol) inmethanol (250 mL) was added a solution of concentrated H₂SO₄ (1.6 mL) inisopropyl alcohol (65 mL) at room temperature (about 22 degrees C.). Tothis suspension was added 30% H₂O₂ in water (65 mL) drop wise over 25minutes. The reaction was monitored by TLC and was completed within 2hours. The solution was diluted with a solution of NaHSO₃ (125 mg) inwater (700 mL). The resulting precipitate was filtered, washed withwater, then methanol: water (1:1), and dried to givebenzhydrylsulfinylacetic acid (47.6 g). ¹H-NMR indicated the desiredproduct was obtained along with ˜10 percent starting material and someimpurities. The compound was triturated with ethanol (100 mL), filteredand dried to give pure benzhydrylsulfinylacetic acid (33.4 g, 49.4%) asa colorless solid. (See Prisinzano, T. et al, Tetrahedron Asymm., 2004,15, 1053-1058)

Example 56

Oxidation of Benzhdrylthioacetic Acid

A 50 L three-necked round bottom flask equipped with a mechanicalstirrer, a 2 L dropping funnel, a nitrogen inlet and an internaltemperature probe was charged with benzhydrylthioacetic acid (3.5 kg,13.54 mol), methanol (14 L) and H₂SO₄ (72 g) solution in isopropylalcohol (6.5 L). To this mixture was added 30% H₂O₂ solution in water(3.75 L) drop wise over 80 minutes maintaining the temperature below 30degrees C. Reaction mixture was further stirred for 7 hours, whichresulted in formation of a crystalline solid. The reaction was monitoredusing TLC and HPLC. The resulting solid was filtered and washed withwater (4.0 L) to give benzhydrylsulfinylacetic acid (2.5 kg) as acolorless solid. The peroxide was quenched with a NaHSO₃ solution.

Example 57

Resolution of Benzhydrylsulfinylacetic Acid UsingS-(−)-α-Methylbenzylamine

To a solution of (±)-benzhydrylsulfinylacetic acid (62.4 g, 0.227 mol)in water (300 mL) at 80 degrees C. was added S-(−)-α-methylbenzyl amine(30 mL, 0.236 mol) and stirred at reflux (101-102 degrees C.) for 10minutes. The solution was gradually cooled to 40 degrees C. and theresulting precipitate was filtered, washed with water and dried to givea colorless solid (71.4 g). The salt was re-crystallized in water (500ml) to give another colorless solid (53.5 g). The salt was thensuspended in water (200 mL), acidified with concentrated HCl (50 mL),and stirred for 10 minutes. The resulting suspension was filtered andwashed with water to give R-(−)-benzhydrylsulfinylacetic acid (21.5 g)as a colorless solid. Chiral purity as determined by HPLC was >99.9% ee.(See U.S. Pat. No. 4,927,855)

Example 58

Amidation of R-(−)-Benzhydrylsulfinylacetic Acid to Give R-(−)-ModafinilUsing N,N-Carbonyl Diimidazole

A 50 L, three-necked round bottom flask equipped with a mechanicalstirrer, a nitrogen inlet and an internal temperature probe was chargedwith R-(−)-benzhydrylsulfinylacetic acid (1.32 kg, 4.81 mol) andtetrahydrofuran (7.0 L). To this slurry was added N,N-carbonyldiimidazole (1.215 kg, 7.49 mol) in tetrahydrofuran (7 L), which gave aclear solution. The solution was then stirred for 30 minutes and NH₃ gas(191 g, 2.5 eq.) was then bubbled through the reaction mixture for 3.5hours. After that time, the volatiles were removed in vacuo to give acrude solid, which was triturated with a 20% methanol solution int-butylmethylether (7.0 L) overnight. The solid material was thencollected and purified further by refluxing of the solid in a 1:1mixture of ethanol and t-butylmethylether (3 L). The reaction was thencooled to room temperature and the solid material was filtered and driedto give R-(−)-modafinil (501 g, 99.6% chemical purity and 100% ee) as acolorless solid.

Example 59

Preparation of Racemic Modafinil Via Activation Using N,N-CarbonylDiimidazole (CDI)

To a suspension of (±)-benzhydrylsulfinylacetic acid (10.0 g, 0.036 mol)in tetrahydrofuran (100 mL) was added N,N-carbonyl diimidazole (7.1 g,0.043 mol) resulting in a clear solution. The solution was stirred for10 minutes and a precipitate formed upon evolution of CO₂. NH₃ gas wasthen bubbled through the reaction mixture for 10 minutes raising thereaction temperature from 16 to 33 degrees C. The reaction mixture wasthen diluted with water and extracted with ethyl acetate (3×50 mL). Theorganic layers were combined, washed with water, brine and dried overNa₂SO₄. The organic layer was then concentrated in vacuo to give crudemodafinil (11.5 g). Recrystallization from 60% aqueous methanol gavepure modafinil (6.0 g) as a colorless solid.

Example 60

Synthesis of (±)-Modafinil from Benzhydrol

To a solution of benzhydrol (30 g, 0.162 mol) and trifluoroacetic acid(15 mL) in dichloromethane (120 ml) was added a solution of methylthioglycolate (0.178 mol) in dichloromethane (30 ml) drop wise over 20minutes. The reaction was stirred at room temperature for 1 hour and asaturated NaHCO₃ solution was added slowly. The organic layer wasseparated and concentrated in vacuo to give crude benzhydrylthioacetate(38.2 g, 89%).

To a solution of NH₄Cl (0.29 mol, 2.0 eq) and NH₄OH (300 ml) in methanol(200 mL) was added a solution of benzhydrylthioacetate (38.2 g, 0.145mol) in methanol (50 ml) maintaining the temperature below 20° C. Thereaction was stirred for 1 hour and diluted with water (100 ml)resulting in the formation of a precipitate. The precipitate wascollected, washed with water and dried to give benzhydrylthioacetamide(31 g) as colorless solid.

Racemic modafinil was obtained from oxidation of benzhydrylthiacetamideusing H₂O₂ following the same method used in the oxidation ofbenzhydrylthioacetic acid in the preparation of R-(−)-modafinil. TABLE I# # MW accept- do- pKa Co-Crystal Former (g/mol) MP (° C.) ClassFunctionality ors nors Molecular Strucutre Values 1-Hydroxy-2- naphthoicacid 188.18 191-192 2 Carboxylic acid, alcohol 1 2

2.7, 13.5 4-aminobenzoic acid 137.14 187-188 2 Amine, carboxylic acid 13

4.7, 4.8 4-aminopyridine 94.11 158-159 3 Amine, pyridine 1 2

10 4-Chlorobenzene- sulfonic acid 192.63 67 1 SO₃H 3 1

0-1 4-ethoxyphenyl urea 180.2 173-174 3 Amide, NH 2 3

˜7-9 7-oxo-DHEA 303 190-192 1 Alcohol, Ketone 3 1

Acesulfame 163.15 123-124 3 SO₂, Amide 4 1

˜5-7 Acetohydroxamic acid 75.07 89-92 3 Amide, NH, OH 2 2

8.7 Adenine 135.13 220 (sub.) 1 Amine, NH 3 3

3.8 Adipic Acid 146.14 152 1 Carboxylic acid 2 2 HOOC(CH₂)₄COOH 4.44,5.44 Alanine 89.09 289-291 1 Amine, carboxillic acid 1 3

2.35, 9.87 Allopurinaol 136.11 >350 3 OH, NH 4 2

10.2 Arginine 174.2 244 (dec.) 1 Amine, COOH 2 7

2.18, 9.09, 13.2 Ascorbic acid 176.12 190-192 1 C═O, OH 6 4

4.17, 11.57 Asparagine 132.12 234-235 1 Amine, amide, COOH 3 5

2.02, 8.5 Aspartic acid 133.1 270-271 1 Amine, COOH 2 4

1.88, 3.65, 9.60 Benzenesulfonic Acid 158.18 43-44 1 SO₃H 2 1

0.70, 1.58 Benzoic acid* 122.12 122-123 2 COOH 1 1

4.19 Caffeine 194.19 238 3 C═O 3 0

Camphoric acid 200.23 186-189 2 Carboxylic acid 2 2

4.72, 5.83 Capric acid 172.27 31.4 1 Carboxylic acid 1 1 CH₃(CH₂)₈COOH4.9 Chrysin 254.24 285 1 Phenol, ether, ketone 2 2

Cinnamic acid 144.2 133 3 Carboxylic acid 1 1

4.4 Citric Acid 192.12 153 1 OH, COOH 4 4

3.13, 4.76, 6.40 Clemizole 325.84 167 1 Pyrrolidine 3 0

Cyclamic acid 179.24 169-170 3 NH, SO₃H 2 2

−2 Cysteine 121.15 — 1 Amine, COOH, SH 2 4

1.71, 8.33, 10.78 Dimethylglycine 103.1 178-192 1 Amine, Carboxylic acid2 1

2.5 D-Ribose 150.13 87 1 Alcohol, ether 1 4

Fumaric acid 116.07 287 1 COOH 2 2

3.03, 4.38 Galactaric acid 210.14 255 (dec) 1 Carboxylic acid, alcohol 26

3.08, 3.63 Genistein 270.24 297-298 1 Alcohol, Phenol, ether, ketone 2 3

Gentisic acid 154.12 199-200 form I, 205 form II 2 Carboxylic acid,alcohol, phenol 1 3

2.93 Glucamine, N-Methyl 195.22 128-129 1 Alcohol, Amine 5 6

8.03(B) Gluconic acid 196.15 131 1 OH, COOH 6 6

3.76 Glucosamine 179.17 88 1 OH 5 6

6.91 Glucuronic acid 194.14 165 1 Carboxylic acid, alcohol, aldehyde 2 5

3.18 Glutamic acid 147.13 160 1 Amine, COOH 2 4

2.19, 4.25, 9.67 Glutamine 146.15 185-186 1 Amine, Amide, COOH 2 5

2.17, 9.13 Glutaric acid 132.11 98—98 1 COOH 2 2

2.7, 4.5 Glycine 75.07 182 1 Amine, COOH 2 3

2.34, 9.6 Glycolic acid 76.05 80 1 OH, COOH 2 2

3.82 Hippuric acid 179.17 187-188 1 Amide, NH, COOH 2 2

3.55 Histidine 155.16 287 (dec.) 1 Amine, COOH, Imidazole 2 4

1.78, 5.97, 8.97 Hydroquinone* 110.11 170-171 2 OH, Phenol 2 2

˜10 Imidazole 68.08 90-91 1 NH 1 1

6.92 Ipriflavone 280.32 115-117 1 Ketone, ether 3 0

Isoleucine 131.17 168-170 (sub.) 1 Amine, COOH 1 3

2.32, 9.76 Lactobionic acid 358.3 128-130 2 Alcohol, carboxylic acid,ether 1 9

3.2 Lauric acid 200.32 44-48 1 Carboxylic acid 1 1 CH₃(CH₂)₁₀COOH ˜4.5Leucine 131.17 145-148 (sub.) 1 Carboxylic acid, amine 1 3

2.36, 9.6 Lysine 146.19 225 (dec.) 1 Amine, COOH 1 5

2.2, 8.9, 10.28 Maleic 116.07 138-139 1 COOH 2 2

1.92, 6.23 Malic acid 134.09 131-132 1 OH, COOH 3 3

3.46, 5.1 Malonic 104.06 135 1 COOH 2 2

2.83, 5.70 Mandelic acid 152.15 119 1 OH, COOH 2 2

3.37 Methionine 149.21 280-282 (dec.) 1 Amine, COOH, S- Me 2 3

2-3, 9 Nicotinamide 122.12 128-131 1 Pyridine, amide 2 2

3.3 Nicotinic acid 123.11 236-237 2 Carboxylic acid pyridine 2 1

2.07(B), 4.85 Orotic acid 156.1 345-346 2 Carboxilic acid, lactam 3 3

5.85, 8.95 Oxalic acid 90.04 189 (dec) 2 Carboxilic acid 2 2

1.27, 4.27 Palmitic acid 256.43 63-64 1 Carboxylic acid 1 1CH₃(CH₂)₁₄COOH 4.9 Pamoic 388.38 280 (dec) 2 Carboxylic acid, phenol 2 4

2.51, 3.1 Phenylalanine 165.19 283 (dec.) 1 Amine, COOH 1 3

˜2, ˜9 Piperazine 86.14 106 1 NH 0 2

9.82(B) Procaine 236.31  61 1 Amine, C═O 2 2

8.9(B) Proline 115.13 220-222 (dec.) 1 COOH, NH 1 2

1.99, 10.6 p-Toluenesulfonic acid 172.2 106-107 2 Sulfonic acid 2 1

−1.34 Pyridoxamine 168 193-194 2 OH, Amine, Pyridine 3 4

˜9 Pyridoxine 170 160 2 Alcohol, Pyridine 3 3

˜9 Pyroglutamic acid 129.12 162 2 Carboxylic acid, Lactam 2 2

3.32 Quercetin 302.24 314 dec. 1 Phenol, ether, ketone 2 5

Resveratrol 228.24 253-255 1 Phenol 0 3

Saccharin 183.19 228-230 1 Amide, C═O, S═O, N—H 3 1

2 Salicylic acid, 4-amino 153.14 150-151 3 COOH, OH, Analine 1 4

3.25, 10, 3.5(B) Salicylic acid 138.12 159 3 COOH, OH 2 2

2.98, 13.82 Sebacic acid 202.25 134.5 1 Carboxylic acid 2 2HOOC(CH₂)₈COOH 4.59, 5.59 Serine 105.09 228 (dec.) 1 Carboxylic acid,amine, OH 2 3

2.21, 9.15 Stearic acid 284.47 70-71 1 Carboxylic acid 1 1CH₃(CH₂)₁₆COOH 4.9 Succinic acid 118.09 185-187 1 Carboxylic acid 2 2

4.21, 5.64 Tartaric acid 150.09 205-206 1 Carboxylic acid 4 4

3.02, 4.36 Threonine 119.12 255-257 (dec.) 1 Amine, COOH, OH 2 4

2.15, 9.12 TRIS 121.13 171-172 2 Amine, OH 3 5

5.91, 8.3 Tryptophan 204.23 289 (dec.) 1 Amine, COOH, Indole 1 4

2.38, 9.39 Tyrosine 181.19 342-344 1 Amine, COOH, OH 2 3

2.2, 9.11, 10.07 Urea 60.06 Dec. 1 C═O, NH2 1 4

˜8 Valine 117.15 315 1 Amine, COOH 1 3

˜4.5, ˜9 Vitamin K5 209.68 280-282 (dec.) 3 Amine, OH 1 3

˜9 Xylitol 152.15 93-95 (I) 2 OH 5 5

˜9

TABLE II Co-crystal Former Co-crystal Former Functional GroupInteracting Group 1,5-Napthalene-disulfonic Acid Sulfonic Acid pyridineketone aldehyde ether ester amide Carboxylic Acid 1-Hydroxy-2-naphthoicacid Carboxylic Acid alcohol ketone thiol amide amine analine phenol1-Hydroxy-2-naphthoic acid alcohol alcohol ketone thiol amide amineanaline phenol 4-Aminobenzoic Acid Amine alcohol ketone thiol amideamine analine phenol 4-Aminobenzoic Acid Carboxylic Acid alcohol ketonethiol amide amine analine phenol 4-aminopyridine Amine alcohol ketonethiol amide amine analine phenol 4-aminopyridine Pyridine *alcoholpyridinium * *amide nitro *amine *Carboxylic Acid4-Chlorobenzene-Sulfonic Acid Sulfonic Acid pyridine ketone aldehydeether ester amide Carboxylic Acid 4-ethoxyphenyl Urea Amide alcoholketone thiol amide amine analine phenol 4-ethoxyphenyl Urea Aminealcohol ketone thiol amide amine analine phenol 7-oxo-DHEA alcoholalcohol ketone thiol amide amine analine phenol 7-oxo-DHEA Ketonealcohol thiol amide amine analine phenol Acesulfame Sulfone pyridineketone aldehyde ether ester amide carboxilic acid Acesulfame Amidealcohol ketone thiol amide amine analine phenol Acetohydroxamic AcidAmide alcohol ketone thiol amide amine analine phenol AcetohydroxamicAcid Amine alcohol ketone thiol amide amine analine phenolAcetohydroxamic Acid Alcohol alcohol ketone thiol amide amine analinephenol Adenine Amine alcohol ketone thiol amide amine analine phenolAdenine N *alcohol pyridinium * *amide nitro *amine *carboxilic acidAdipic acid Carboxylic Acid alcohol ketone thiol amide amine analinephenol Alanine Amine alcohol ketone thiol amide amine analine phenolAlanine Carboxylic Acid alcohol ketone thiol amide amine analine phenolAllopurinaol Alcohol alcohol ketone thiol amide amine analine phenolAllopurinaol Amine alcohol ketone thiol amide amine analine phenolArginine Amine alcohol ketone thiol amide amine analine phenol ArginineCarboxylic Acid alcohol ketone thiol amide amine analine phenol AscorbicAcid Ketone alcohol thiol amide amine analine phenol Ascorbic AcidAlcohol alcohol ketone thiol amide amine analine phenol Ascorbic AcidCarboxylic Acid alcohol ketone thiol amide amine analine phenolCo-crystal Former Interacting Group 1,5-Napthalene-disulfonic Acid aminemetals thioether sulfate alcohol 1-Hydroxy-2-naphthoic acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehyde ester1-Hydroxy-2-naphthoic acid phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde ester 4-Aminobenzoic Acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehyde4-Aminobenzoic Acid phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde 4-aminopyridine phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde 4-aminopyridine*sulfonamide *ketone ether triazole ammonium oxime *chlorine4-Chlorobenzene-Sulfonic Acid amine metals thioether sulfate alcohol4-ethoxyphenyl Urea phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde 4-ethoxyphenyl Urea phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde 7-oxo-DHEAphosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde ester 7-oxo-DHEA phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde Acesulfame amine metals thioethersulfate alcohol Acesulfame phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde Acetohydroxamic Acid phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde AcetohydroxamicAcid phosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Acetohydroxamic Acid phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde Adenine phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Adenine *sulfonamide*ketone ether triazole ammonium oxime *chlorine Adipic acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehyde Alaninephosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Alanine phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Allopurinaol phosphate sulfate sulfone nitratepyridine Carboxylic Acid metals aldehyde Allopurinaol phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde Argininephosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Arginine phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Ascorbic Acid phosphate sulfate sulfone nitratepyridine Carboxylic Acid metals aldehyde Ascorbic Acid phosphate sulfatesulfone nitrate pyridine Carboxylic Acid metals aldehyde Ascorbic Acidphosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Co-crystal Former Interacting Group 1,5-Napthalene-disulfonicAcid 1-Hydroxy-2-naphthoic acid ether cyano furan bromine chlorines-heterocyclic pyridine 1-Hydroxy-2-naphthoic acid ether cyano furanbromine chlorine s-heterocyclic pyridine 4-Aminobenzoic Acid ester ethercyano furan bromine chlorine s-heterocyclic 4-Aminobenzoic Acid esterether cyano furan bromine chlorine s-heterocyclic 4-aminopyridine esterether cyano furan bromine chlorine s-heterocyclic 4-aminopyridine thioln-heterocyclic thionedisulfide pyrrolidindione iodine hydrazonethiocyanate *bromine ring 4-Chlorobenzene-Sulfonic Acid 4-ethoxyphenylUrea ester ether cyano furan bromine chlorine s-heterocyclic4-ethoxyphenyl Urea ester ether cyano furan bromine chlorines-heterocyclic 7-oxo-DHEA ether cyano furan bromine chlorines-heterocyclic pyridine 7-oxo-DHEA ester ether cyano furan brominechlorine s-heterocyclic Acesulfame Acesulfame ester ether cyano furanbromine chlorine s-heterocyclic Acetohydroxamic Acid ester ether cyanofuran bromine chlorine s-heterocyclic Acetohydroxamic Acid ester ethercyano furan bromine chlorine s-heterocyclic Acetohydroxamic Acid esterether cyano furan bromine chlorine s-heterocyclic Adenine ester ethercyano furan bromine chlorine s-heterocyclic Adenine thiol n-heterocyclicthionedisulfide pyrrolidindione iodine hydrazone thiocyanate *brominering Adipic acid ester ether cyano furan bromine chlorine s-heterocyclicAlanine ester ether cyano furan bromine chlorine s-heterocyclic Alanineester ether cyano furan bromine chlorine s-heterocyclic Allopurinaolester ether cyano furan bromine chlorine s-heterocyclic Allopurinaolester ether cyano furan bromine chlorine s-heterocyclic Arginine esterether cyano furan bromine chlorine s-heterocyclic Arginine ester ethercyano furan bromine chlorine s-heterocyclic Ascorbic Acid ester ethercyano furan bromine chlorine s-heterocyclic Ascorbic Acid ester ethercyano furan bromine chlorine s-heterocyclic Ascorbic Acid ester ethercyano furan bromine chlorine s-heterocyclic Co-crystal FormerInteracting Group 1,5-Napthalene-disulfonic Acid 1-Hydroxy-2-naphthoicacid cyano n-heterocyclic ketone phosphate ester fluorine carbamate1-Hydroxy-2-naphthoic acid cyano n-heterocyclic ketone phosphate esterfluorine carbamate 4-Aminobenzoic Acid pyridine cyano n-heterocyclicketone phosphate ester fluorine 4-Aminobenzoic Acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine 4-aminopyridine pyridinecyano n-heterocyclic ketone phosphate ester fluorine 4-aminopyridinehydroxamic acid cyano carboxamide *sulfonic acid *phosphoric acidN-oxide 4-Chlorobenzene-Sulfonic Acid 4-ethoxyphenyl Urea pyridine cyanon-heterocyclic ketone phosphate ester fluorine 4-ethoxyphenyl Ureapyridine cyano n-heterocyclic ketone phosphate ester fluorine 7-oxo-DHEAcyano n-heterocyclic ketone phosphate ester fluorine carbamate7-oxo-DHEA pyridine cyano n-heterocyclic ketone phosphate ester fluorineAcesulfame Acesulfame pyridine cyano n-heterocyclic ketone phosphateester fluorine Acetohydroxamic Acid pyridine cyano n-heterocyclic ketonephosphate ester fluorine Acetohydroxamic Acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine Acetohydroxamic Acidpyridine cyano n-heterocyclic ketone phosphate ester fluorine Adeninepyridine cyano n-heterocyclic ketone phosphate ester fluorine Adeninehydroxamic acid cyano carboxamide *sulfonic acid *phosphoric acidN-oxide Adipic acid pyridine cyano n-heterocyclic ketone phosphate esterfluorine Alanine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Alanine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Allcpurinaol pyridine cyano n-heterocyclic ketone phosphateester fluorine Allcpurinaol pyridine cyano n-heterocyclic ketonephosphate ester fluorine Arginine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Arginine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Ascorbic Acid pyridine cyano n-heterocyclicketone phosphate ester fluorine Ascorbic Acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine Ascorbic Acid pyridinecyano n-heterocyclic ketone phosphate ester fluorine Co-crystal FormerInteracting Group 1,5-Napthalene-disulfonic Acid 1-Hydroxy-2-naphthoicimidazole BF4 acid 1-Hydroxy-2-naphthoic imidazole BF4 acid4-Aminobenzoic Acid carbamate imidazole BF4 N—SO2 thiourea iodine4-Aminobenzoic Acid carbamate imidazole BF4 N—SO2 thiourea iodine4-aminopyridine carbamate imidazole BF4 N—SO2 thiourea iodine4-aminopyridine ester ether fluorine acetate thionedithiadiazocyclopentadienyl 4-Chlorobenzene-Sulfonic Acid 4-ethoxyphenylUrea carbamate imidazole BF4 N—SO2 thiourea iodine epoxide peroxide4-ethoxyphenyl Urea carbamate imidazole BF4 N—SO2 thiourea iodine7-oxo-DHEA imidazole BF4 7-oxo-DHEA carbamate imidazole BF4 N—SO2thiourea iodine Acesulfame Acesulfame carbamate imidazole BF4 N—SO2thiourea iodine epoxide peroxide Acetohydroxamic Acid carbamateimidazole BF4 N—SO2 thiourea iodine epoxide peroxide AcetohydroxamicAcid carbamate imidazole BF4 N—SO2 thiourea iodine Acetohydroxamic Acidcarbamate imidazole BF4 N—SO2 thiourea iodine epoxide Adenine carbamateimidazole BF4 N—SO2 thiourea iodine Adenine ester ether fluorine acetatethione dithiadiazocyclopentadienyl Adipic acid carbamate imidazole BF4N—SO2 thiourea iodine Alanine carbamate imidazole BF4 N—SO2 thioureaiodine Alanine carbamate imidazole BF4 N—SO2 thiourea iodineAllopurinaol carbamate imidazole BF4 N—SO2 thiourea iodine epoxideAllopurinaol carbamate imidazole BF4 N—SO2 thiourea iodine Argininecarbamate imidazole BF4 N—SO2 thiourea iodine Arginine carbamateimidazole BF4 N—SO2 thiourea iodine Ascorbic Acid carbamate imidazoleBF4 N—SO2 thiourea iodine Ascorbic Acid carbamate imidazole BF4 N—SO2thiourea iodine epoxide Ascorbic Acid carbamate imidazole BF4 N—SO2thiourea iodine Co-crystal Former Co-crystal Former Functional GroupInteracting Group Asparagine Amine alcohol ketone thiol amide amineanaline phenol Asparagine Amide alcohol ketone thiol amide amine analinephenol Asparagine Carboxylic Acid alcohol ketone thiol amide amineanaline phenol Aspartic Acid Amine alcohol ketone thiol amide amineanaline phenol Aspartic Acid Carboxylic Acid alcohol ketone thiol amideamine analine phenol Benzenesulfonic Acid Sulfonic Acid pyridine ketonealdehyde ether ester amide Carboxylic Acid Benzoic Acid Carboxylic Acidalcohol ketone thiol amide amine analine phenol Caffeine Ketone alcoholthiol amide amine analine phenol Camphoric acid Carboxylic Acid alcoholketone thiol amide amine analine phenol Capric acid Carboxylic Acidalcohol ketone thiol amide amine analine phenol Genistein Ketone alcoholthiol amide amine analine phenol Genistein Phenol amine amide sulfoxiden pyridine cyano aldehyde Genistein Ether aromatic-N amide aminearomatic_s Sp2 amine sulfoxide chlorate Cinnamic acid Carboxylic Acidalcohol ketone thiol amide amine analine phenol Citric Acid Alcoholalcohol ketone thiol amide amine analine phenol Citric Acid CarboxylicAcid alcohol ketone thiol amide amine analine phenol ClemizolePyrrolidine *alcohol pyridinium * *amide nitro *amine *carboxilic acidCyclamic Acid Amine alcohol ketone thiol amide amine analine phenolCyclamic Acid Sulfonic Acid pyridine ketone aldehyde ether ester amideCarboxylic Acid Cysteine Amine alcohol ketone thiol amide amine analinephenol Cysteine Carboxylic Acid alcohol ketone thiol amide amine analinephenol Cysteine Thiol carboxylic sodium aldehyde ketone —N cadmium acidDimethylglycine Carboxylic Acid alcohol ketone thiol amide amine analinephenol Dimethylglycine Amine alcohol ketone thiol amide amine analinephenol D-ribose Ether aromatic-N amide amine aromatic_s Sp2 aminesulfoxide chlorate D-ribose Alcohol alcohol ketone thiol amide amineanaline phenol Fumaric Acid Carboxylic Acid alcohol ketone thiol amideamine analine phenol Galactaric acid Carboxylic Acid alcohol ketonethiol amide amine analine phenol Galactaric acid alcohol alcohol ketonethiol amide amine analine phenol Chrysin Ketone alcohol — thiol amideamine analine phenol Co-crystal Former Interacting Group Asparaginephosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Asparagine phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde Asparagine phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Aspartic Acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehydeAspartic Acid phosphate sulfate sulfone nitrate pyridine carboxilic acidmetals aldehyde Benzenesulfonic Acid amine metals thioether sulfatealcohol Benzoic Acid phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Caffeine phosphate sulfate sulfonenitrate pyridine Carboxylic Acid metals aldehyde Camphoric acidphosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Capric acid phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Genistein phosphate sulfate sulfonenitrate pyridine Carboxylic Acid metals aldehyde Genistein alchoholester ether n-oxide chlorine fluorine bromine Genistein chlorine cyanoester amine nitro nitrate bromine aldehyde Cinnamic acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehyde CitricAcid phosphate sulfate sulfone nitrate pyridine Carboxylic Acid metalsaldehyde Citric Acid phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Clemizole *sulfonamide *ketone ethertriazole ammonium oxime *chlorine Cyclamic Acid phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde Cyclamic Acidamine metals thioether sulfate alcohol Cysteine phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde Cysteinephosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Cysteine arsenic chlorine alcohol potassium Ru Rb SbDimethylglycine phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Dimethylglycine phosphate sulfate sulfone nitratepyridine carboxilic acid metals aldehyde D-ribose chlorine cyano esteramine nitro nitrate bromine aldehyde D-ribose phosphate sulfate sulfonenitrate pyridine Carboxylic Acid metals aldehyde Fumaric Acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehydeGalactaric acid phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Galactaric acid phosphate sulfate sulfone nitratepyridine carboxilic acid metals aldehyde ester Chrysin phosphate sulfatesulfone nitrate pyridine Carboxylic Acid metals aldehyde Co-crystalFormer Interacting Group Asparagine ester ether cyano furan brominechlorine s-heterocyclic Asparagine ester ether cyano furan brominechlorine s-heterocyclic Asparagine ester ether cyano furan brominechlorine s-heterocyclic Aspartic Acid ester ether cyano furan brominechlorine s-heterocyclic Aspartic Acid ester ether cyano furan brominechlorine s-heterocyclic Benzenesulfonic Acid Benzoic Acid ester ethercyano furan bromine chlorine s-heterocyclic Caffeine ester ether cyanofuran bromine chlorine s-heterocyclic Camphoric acid ester ether cyanofuran bromine chlorine s-heterocyclic Capric acid ester ether cyanofuran bromine chlorine s-heterocyclic Genistein ester ether cyano furanbromine chlorine s-heterocyclic Genistein iodine ketone sulfonic acidsulfate phosphate phosphonic acid carboxylic acid nitro Genistein ketoneperoxide epoxide heterocyclic-S iodine ester Cinnamic acid ester ethercyano furan bromine chlorine s-heterocyclic Citric Acid ester ethercyano furan bromine chlorine s-heterocyclic Citric Acid ester ethercyano furan bromine chlorine s-heterocyclic Clemizole thioln-heterocyclic thionedisulfide pyrrolidindione iodine hydrazonethiocyanate *bromine ring Cyclamic Acid ester ether cyano furan brominechlorine s-heterocyclic Cyclamic Acid Cysteine ester ether cyano furanbromine chlorine s-heterocyclic Cysteine ester ether cyano furan brominechlorine s-heterocyclic Cysteine Dimethylglycine ester ether cyano furanbromine chlorine s-heterocyclic Dimethylglycine ester ether cyano furanbromine chlorine s-heterocyclic D-ribose ketone peroxide epoxideheterocyclic-S iodine ester D-ribose ester ether cyano furan brominechlorine s-heterocyclic Fumaric Acid ester ether cyano furan brominechlorine s-heterocyclic Galactaric acid ester ether cyano furan brominechlorine s-heterocyclic Galactaric acid ether cyano furan brominechlorine s-heterocyclic pyridine Chrysin ester ether cyano furan brominechlorine s-heterocyclic Co-crystal Former Interacting Group Asparaginepyridine cyano n-heterocyclic ketone phosphate ester fluorine Asparaginepyridine cyano n-heterocyclic ketone phosphate ester fluorine Asparaginepyridine cyano n-heterocyclic ketone phosphate ester fluorine AsparticAcid pyridine cyano n-heterocyclic ketone phosphate ester fluorineAspartic Acid pyridine cyano n-heterocyclic ketone phosphate esterfluorine Benzenesulfonic Acid Benzoic Acid pyridine cyano n-heterocyclicketone phosphate ester fluorine Caffeine pyridine cyano n-heterocyclicketone phosphate ester fluorine Camphoric acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine Capric acid pyridinecyano n-heterocyclic ketone phosphate ester fluorine Genistein pyridinecyano n-heterocyclic ketone phosphate ester fluorine Genistein sulfoneanaline Genistein ether carboxylic acid sulfate sulfone alcohol Cinnamicacid pyridine cyano n-heterocyclic ketone phosphate ester fluorineCitric Acid pyridine cyano n-heterocyclic ketone phosphate esterfluorine Citric Acid pyridine cyano n-heterocyclic ketone phosphateester fluorine Clemizole hydroxamic acid cyano carboxamide *sulfonicacid *phosphoric acid N-oxide Cyclamic Acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine Cyclamic Acid Cysteinepyridine cyano n-heterocyclic ketone phosphate ester fluorine Cysteinepyridine cyano n-heterocyclic ketone phosphate ester fluorine CysteineDimethylglycine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Dimethylglycine pyridine cyano n-heterocyclic ketone phosphateester fluorine D-ribose ether carboxylic acid sulfate sulfone alcoholD-ribose pyridine cyano n-heterocyclic ketone phosphate ester fluorineFumaric Acid pyridine cyano n-heterocyclic ketone phosphate esterfluorine Galactaric acid pyridine cyano n-heterocyclic ketone phosphateester fluorine Galactaric acid cyano n-heterocyclic ketone phosphateester fluorine carbamate Chrysin pyridine cyano n-heterocyclic ketonephosphate ester fluorine Co-crystal Former Interacting Group Asparaginecarbamate imidazole BF4 N—SO2 thiourea iodine Asparagine carbamateimidazole BF4 N—SO2 thiourea iodine epoxide peroxide Asparaginecarbamate imidazole BF4 N—SO2 thiourea iodine Aspartic Acid carbamateimidazole BF4 N—SO2 thiourea iodine Aspartic Acid carbamate imidazoleBF4 N—SO2 thiourea iodine Benzenesulfonic Acid Benzoic Acid carbamateimidazole BF4 N—SO2 thiourea iodine Caffeine carbamate imidazole BF4N—SO2 thiourea iodine Camphoric acid carbamate imidazole BF4 N—SO2thiourea iodine Capric acid carbamate imidazole BF4 N—SO2 thioureaiodine Genistein carbamate imidazole BF4 N—SO2 thiourea iodine GenisteinGenistein phospphate cyanamide Cinnamic acid carbamate imidazole BF4N—SO2 thiourea iodine Citric Acid carbamate imidazole BF4 N—SO2 thioureaiodine epoxide Citric Acid carbamate imidazole BF4 N—SO2 thiourea iodineClemizole ester ether fluorine acetate thionedithiadiazocyclopentadienyl Cyclamic Acid carbamate imidazole BF4 N—SO2thiourea iodine Cyclamic Acid Cysteine carbamate imidazole BF4 N—SO2thiourea iodine Cysteine carbamate imidazole BF4 N—SO2 thiourea iodineCysteine Dimethylglycine carbamate imidazole BF4 N—SO2 thiourea iodineDimethylglycine carbamate imidazole BF4 N—SO2 thiourea iodine D-ribosephospphate cyanamide D-ribose carbamate imidazole BF4 N—SO2 thioureaiodine epoxide Fumaric Acid carbamate imidazole BF4 N—SO2 thioureaiodine Galactaric acid carbamate imidazole BF4 N—SO2 thiourea iodineGalactaric acid imidazole BF4 Chrysin carbamate imidazole BF4 N—SO2thiourea iodine Co-crystal Co-crystal Former Former Functional GroupInteracting Group Chrysin Phenol amine amide sulfoxide n pyridine cyanoaldehyde Chrysin Ether aromatic-N amide amine aromatic_s Sp2 aminesulfoxide chlorate Gentisic acid Carboxylic Acid alcohol ketone thiolamide amine analine phenol Gentisic acid Phenol amine amide sulfoxide npyridine cyano aldehyde Glucamine, N-methyl alcohol alcohol ketone thiolamide amine analine phenol Glucamine, N-methyl Amine alcohol ketonethiol amide amine analine phenol Gluconic Acid Alcohol alcohol ketonethiol amide amine analine phenol Gluconic Acid Carboxylic Acid alcoholketone thiol amide amine analine phenol Glucosamine alcohol alcoholketone thiol amide amine analine phenol Glucuronic acid Carboxylic Acidalcohol ketone thiol amide amine analine phenol Glucuronic acid alcoholalcohol ketone thiol amide amine analine phenol Glucuronic acid Aldehydealcohol ketone thiol amide amine analine phenol Glutamic Acid Aminealcohol ketone thiol amide amine analine phenol Glutamic Acid CarboxylicAcid alcohol ketone thiol amide amine analine phenol Glutamine Aminealcohol ketone thiol amide amine analine phenol Glutamine Amide alcoholketone thiol amide amine analine phenol Glutamine Carboxylic Acidalcohol ketone thiol amide amine analine phenol Glutaric Acid CarboxylicAcid alcohol ketone thiol amide amine analine phenol Glycine Aminealcohol ketone thiol amide amine analine phenol Glycine Carboxylic Acidalcohol ketone thiol amide amine analine phenol Glycolic Acid Alcoholalcohol ketone thiol amide amine analine phenol Glycolic Acid CarboxylicAcid alcohol ketone thiol amide amine analine phenol Hippuric Acid Amidealcohol ketone thiol amide amine analine phenol Hippuric Acid Aminealcohol ketone thiol amide amine analine phenol Hippuric Acid CarboxylicAcid alcohol ketone thiol amide amine analine phenol Histidine Aminealcohol ketone thiol amide amine analine phenol Histidine CarboxylicAcid alcohol ketone thiol amide amine analine phenol Histidine Imidazoleimidazole chlorine acetamide carboxylate thione nitro HydroquinoneAlcohol alcohol ketone thiol amide amine analine phenol HydroquinonePhenol amine amide sulfoxide n pyridine cyano aldehyde Imidazole Aminealcohol ketone thiol amide amine analine phenol Co-crystal FormerInteracting Group Chrysin alchohol ester ether n-oxide chlorine fluorinebromine Chrysin chlorine cyano ester amine nitro nitrate brominealdehyde Gentisic acid phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Gentisic acid alchohol ester ethern-oxide chlorine fluorine bromine Glucamine, N-methyl phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde esterGlucamine, N-methyl phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Gluconic Acid phosphate sulfate sulfonenitrate pyridine Carboxylic Acid metals aldehyde Gluconic Acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehydeGlucosamine phosphate sulfate sulfone nitrate pyridine Carboxylic Acidmetals aldehyde Glucuronic acid phosphate sulfate sulfone nitratepyridine carboxilic acid metals aldehyde Glucuronic acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehyde esterGlucuronic acid phosphate sulfate sulfone nitrate pyridine aromaticcarboxilic acid metals aldehyde Glutamic Acid phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Glutamic Acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehydeGlutamine phosphate sulfate sulfone nitrate pyridine carboxilic acidmetals aldehyde Glutamine phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde Glutamine phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Glutaric Acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehyde Glycinephosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Glycine phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Glycolic Acid phosphate sulfate sulfone nitratepyridine Carboxylic Acid metals aldehyde Glycolic Acid phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde Hippuric Acidphosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Hippuric Acid phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Hippuric Acid phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Histidine phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehydeHistidine phosphate sulfate sulfone nitrate pyridine carboxilic acidmetals aldehyde Histidine cyanamide ketone cyano Carboxylic Acid alcoholthiol amine phosphinic acid hemihydrate Hydroquinone phosphate sulfatesulfone nitrate pyridine Carboxylic Acid metals aldehyde Hydroquinonealchohol ester ether n-oxide chlorine fluorine bromine Imidazolephosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Co-crystal Former Interacting Group Chrysin iodine ketonesulfonic acid sulfate phosphate phosphonic acid carboxylic acid nitroChrysin ketone peroxide epoxide heterocyclic-S iodine ester Gentisicacid ester ether cyano furan bromine chlorine s-heterocyclic Gentisicacid iodine ketone sulfonic acid sulfate phosphate phosphonic acidcarboxylic acid nitro Glucamine, N-methyl ether cyano furan brominechlorine s-heterocyclic pyridine Glucamine, N-methyl ester ether cyanofuran bromine chlorine s-heterocyclic Gluconic Acid ester ether cyanofuran bromine chlorine s-heterocyclic Gluconic Acid ester ether cyanofuran bromine chlorine s-heterocyclic Glucosamine ester ether cyanofuran bromine chlorine s-heterocyclic Glucuronic acid ester ether cyanofuran bromine chlorine s-heterocyclic Glucuronic acid ether cyano furanbromine chlorine s-heterocyclic pyridine Glucuronic acid ester ethercyano furan bromine chlorine s-heterocyclic Glutamic Acid ester ethercyano furan bromine chlorine s-heterocyclic Glutamic Acid ester ethercyano furan bromine chlorine s-heterocyclic Glutamine ester ether cyanofuran bromine chlorine s-heterocyclic Glutamine ester ether cyano furanbromine chlorine s-heterocyclic Glutamine ester ether cyano furanbromine chlorine s-heterocyclic Glutaric Acid ester ether cyano furanbromine chlorine s-heterocyclic Glycine ester ether cyano furan brominechlorine s-heterocyclic Glycine ester ether cyano furan bromine chlorines-heterocyclic Glycolic Acid ester ether cyano furan bromine chlorines-heterocyclic Glycolic Acid ester ether cyano furan bromine chlorines-heterocyclic Hippuric Acid ester ether cyano furan bromine chlorines-heterocyclic Hippuric Acid ester ether cyano furan bromine chlorines-heterocyclic Hippuric Acid ester ether cyano furan bromine chlorines-heterocyclic Histidine ester ether cyano furan bromine chlorines-heterocyclic Histidine ester ether cyano furan bromine chlorines-heterocyclic Histidine chlorine sulfonyl sulfoxide amide fluorinesulfonate ester Hydroquinone ester ether cyano furan bromine chlorines-heterocyclic Hydroquinone iodine ketone sulfonic acid sulfatephosphate phosphonic acid carboxylic acid nitro Imidazole ester ethercyano furan bromine chlorine s-heterocyclic Co-crystal FormerInteracting Group Chrysin sulfone analine Chrysin ether carboxylic acidsulfate sulfone alcohol Gentisic acid pyridine cyano n-heterocyclicketone phosphate ester fluorine Gentisic acid sulfone analine Glucamine,N-methyl cyano n-heterocyclic ketone phosphate ester fluorine carbamateGlucamine, N-methyl pyridine cyano n-heterocyclic ketone phosphate esterfluorine Gluconic Acid pyridine cyano n-heterocyclic ketone phosphateester fluorine Gluconic Acid pyridine cyano n-heterocyclic ketonephosphate ester fluorine Glucosamine pyridine cyano n-heterocyclicketone phosphate ester fluorine Glucuronic acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine Glucuronic acid cyanon-heterocyclic ketone phosphate ester fluorine carbamate Glucuronic acidpyridine cyano n-heterocyclic ketone phosphate ester fluorine GlutamicAcid pyridine cyano n-heterocyclic ketone phosphate ester fluorineGlutamic Acid pyridine cyano n-heterocyclic ketone phosphate esterfluorine Glutamine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Glutamine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Glutamine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Glutaric Acid pyridine cyano n-heterocyclic ketone phosphateester fluorine Glycine pyridine cyano n-heterocyclic ketone phosphateester fluorine Glycine pyridine cyano n-heterocyclic ketone phosphateester fluorine Glycolic Acid pyridine cyano n-heterocyclic ketonephosphate ester fluorine Glycolic Acid pyridine cyano n-heterocyclicketone phosphate ester fluorine Hippuric Acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine Hippuric Acid pyridinecyano n-heterocyclic ketone phosphate ester fluorine Hippuric Acidpyridine cyano n-heterocyclic ketone phosphate ester fluorine Histidinepyridine cyano n-heterocyclic ketone phosphate ester fluorine Histidinepyridine cyano n-heterocyclic ketone phosphate ester fluorine HistidineHydroquinone pyridine cyano n-heterocyclic ketone phosphate esterfluorine Hydroquinone sulfone analine Imidazole pyridine cyanon-heterocyclic ketone phosphate ester fluorine Co-crystal FormerInteracting Group Chrysin Chrysin phospphate cyanamide Gentisic acidcarbamate imidazole BF4 N—SO2 thiourea iodine Gentisic acid Glucamine,N-methyl imidazole BF4 Glucamine, N-methyl carbamate imidazole BF4 N—SO2thiourea iodine Gluconic Acid carbamate imidazole BF4 N—SO2 thioureaiodine epoxide Gluconic Acid carbamate imidazole BF4 N—SO2 thioureaiodine Glucosamine carbamate imidazole BF4 N—SO2 thiourea iodine epoxideGlucuronic acid carbamate imidazole BF4 N—SO2 thiourea iodine Glucuronicacid imidazole BF4 Glucuronic acid carbamate imidazole BF4 alkanearomatic N—SO2 thiourea iodine epoxide Glutamic Acid carbamate imidazoleBF4 N—SO2 thiourea iodine Glutamic Acid carbamate imidazole BF4 N—SO2thiourea iodine Glutamine carbamate imidazole BF4 N—SO2 thiourea iodineGlutamine carbamate imidazole BF4 N—SO2 thiourea iodine epoxide peroxideGlutamine carbamate imidazole BF4 N—SO2 thiourea iodine Glutaric Acidcarbamate imidazole BF4 N—SO2 thiourea iodine Glycine carbamateimidazole BF4 N—SO2 thiourea iodine Glycine carbamate imidazole BF4N—SO2 thiourea iodine Glycolic Acid carbamate imidazole BF4 N—SO2thiourea iodine epoxide Glycolic Acid carbamate imidazole BF4 N—SO2thiourea iodine Hippuric Acid carbamate imidazole BF4 N—SO2 thioureaiodine epoxide peroxide Hippuric Acid carbamate imidazole BF4 N—SO2thiourea iodine Hippuric Acid carbamate imidazole BF4 N—SO2 thioureaiodine Histidine carbamate imidazole BF4 N—SO2 thiourea iodine Histidinecarbamate imidazole BF4 N—SO2 thiourea iodine Histidine Hydroquinonecarbamate imidazole BF4 N—SO2 thiourea iodine epoxide HydroquinoneImidazole carbamate imidazole BF4 N—SO2 thiourea iodine Co-crystalFormer Co-crystal Former Functional Group Interacting Group IpriflavoneEther aromatic-N amide amine aromatic_s Sp2 amine sulfoxide chlorateIpriflavone Ketone alcohol thiol amide amine analine phenol IsoleucineAmine alcohol ketone thiol amide amine analine phenol IsoleucineCarboxylic Acid alcohol ketone thiol amide amine analine phenollactobionic acid Carboxylic Acid alcohol ketone thiol amide amineanaline phenol Lactobionic acid alcohol alcohol ketone thiol amide amineanaline phenol Lactobionic acid Ether aromatic-N amide amine aromatic_sSp2 amine sulfoxide chlorate Lauric acid Carboxylic Acid alcohol ketonethiol amide amine analine phenol Leucine Carboxylic Acid alcohol ketonethiol amide amine analine phenol Leucine Amine alcohol ketone thiolamide amine analine phenol Lysine Amine alcohol ketone thiol amide amineanaline phenol Lysine Carboxylic Acid alcohol ketone thiol amide amineanaline phenol Maleic Carboxylic Acid alcohol ketone thiol amide amineanaline phenol Malic Acid Alcohol alcohol ketone thiol amide amineanaline phenol Malic Acid Carboxylic Acid alcohol ketone thiol amideamine analine phenol Malonic Carboxylic Acid alcohol ketone thiol amideamine analine phenol Mandelic Acid Alcohol alcohol ketone thiol amideamine analine phenol Mandelic Acid Carboxylic Acid alcohol ketone thiolamide amine analine phenol Methionine Amine alcohol ketone thiol amideamine analine phenol Methionine Carboxylic Acid alcohol ketone thiolamide amine analine phenol Methionine Thioether -N amide amine _s Sp2amine sulfoxide chlorate Nicotinamide Pyridine *alcohol * *amide nitro*amine *Carboxylic Acid Nicotinamide Amide alcohol ketone thiol amideamine analine phenol Nicotinic Acid Carboxylic Acid alcohol ketone thiolamide amine analine phenol Nicotinic Acid Pyridine *alcohol * *amidenitro *amine *Carboxylic Acid Orotic acid Carboxylic Acid alcohol ketonethiol amide amine analine phenol Orotic acid Lactam alcohol ketone thiolamide amine analine phenol Oxalic acid Carboxylic Acid alcohol ketonethiol amide amine analine phenol Palmitic acid Carboxylic Acid alcoholketone thiol amide amine analine phenol Pamoic acid Carboxylic Acidalcohol ketone thiol amide amine analine phenol Pamoic acid alcoholalcohol ketone thiol amide amine analine phenol Pamoic acid Phenol amineamide sulfoxide n pyridine cyano aldehyde Co-crystal Former InteractingGroup Ipriflavone chlorine cyano ester amine nitro nitrate brominealdehyde Ipriflavone phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde Isoleucine phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Isoleucine phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehydelactobionic acid phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Lactobionic acid phosphate sulfate sulfone nitratepyridine carboxilic acid metals aldehyde ester Lactobionic acid chlorinecyano ester amine nitro nitrate bromine aldehyde Lauric acid phosphatesulfate sulfone nitrate pyridine carboxilic acid aldehyde Leucinephosphate sulfate sulfone nitrate pyridine Carboxylic Acid metalsaldehyde Leucine phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Lysine phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Lysine phosphate sulfate sulfone nitratepyridine carboxilic acid metals aldehyde Maleic phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde Malic Acidphosphate sulfate sulfone nitrate pyridine Carboxylic Acid metalsaldehyde Malic Acid phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Malonic phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Mandelic Acid phosphatesulfate sulfone nitrate pyridine Carboxylic Acid metals aldehydeMandelic Acid phosphate sulfate sulfone nitrate pyridine carboxilic acidmetals aldehyde Methionine phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Methionine phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Methionine chlorinecyano ester amine nitro nitrate bromine aldehyde Nicotinamide*sulfonamide *ketone ether triazole ammonium oxime *chlorineNicotinamide phosphate sulfate sulfone nitrate pyridine Carboxylic Acidmetals aldehyde Nicotinic Acid phosphate sulfate sulfone nitratepyridine Carboxylic Acid metals aldehyde Nicotinic Acid *sulfonamide*ketone ether triazole ammonium oxime *chlorine Orotic acid phosphatesulfate sulfone nitrate pyridine carboxilic acid aldehyde Orotic acidphosphate sulfate sulfone nitrate pyridine Carboxylic Acid metalsaldehyde Oxalic acid phosphate sulfate sulfone nitrate pyridinecarboxilic acid aldehyde Palmitic acid phosphate sulfate sulfone nitratepyridine carboxilic acid aldehyde Pamoic acid phosphate sulfate sulfonenitrate pyridine carboxilic acid aldehyde Pamoic acid phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde ester Pamoicacid alchohol ester ether n-oxide chlorine fluorine bromine Co-crystalFormer Interacting Group Ipriflavone ketone peroxide epoxideheterocyclic-S iodine ester Ipriflavone ester ether cyano furan brominechlorine s-heterocyclic Isoleucine ester ether cyano furan brominechlorine s-heterocyclic Isoleucine ester ether cyano furan brominechlorine s-heterocyclic lactobionic acid ester ether cyano furan brominechlorine s-heterocyclic Lactobionic acid ether cyano furan brominechlorine s-heterocyclic pyridine Lactobionic acid ketone peroxideepoxide heterocyclic-S iodine ester Lauric acid ester ether cyano furanbromine chlorine s-heterocyclic Leucine ester ether cyano furan brominechlorine s-heterocyclic Leucine ester ether cyano furan bromine chlorines-heterocyclic Lysine ester ether cyano furan bromine chlorines-heterocyclic Lysine ester ether cyano furan bromine chlorines-heterocyclic Maleic ester ether cyano furan bromine chlorines-heterocyclic Malic Acid ester ether cyano furan bromine chlorines-heterocyclic Malic Acid ester ether cyano furan bromine chlorines-heterocyclic Malonic ester ether cyano furan bromine chlorines-heterocyclic Mandelic Acid ester ether cyano furan bromine chlorines-heterocyclic Mandelic Acid ester ether cyano furan bromine chlorines-heterocyclic Methionine ester ether cyano furan bromine chlorines-heterocyclic Methionine ester ether cyano furan bromine chlorines-heterocyclic Methionine ketone peroxide epoxide Ag Se heterocyclic-Siodine ester Nicotinamide thiol n-heterocyclic thionedisulfidepyrrolidindione iodine hydrazone thiocyanate *bromine ring Nicotinamideester ether cyano furan bromine chlorine s-heterocyclic Nicotinic Acidester ether cyano furan bromine chlorine s-heterocyclic Nicotinic Acidthiol n-heterocyclic thionedisulfide pyrrolidindione iodine hydrazonethiocyanate *bromine ring Orotic acid ester ether cyano furan brominechlorine s-heterocyclic Orotic acid ester ether cyano furan brominechlorine s-heterocyclic Oxalic acid ester ether cyano furan brominechlorine s-heterocyclic Palmitic acid ester ether cyano furan brominechlorine s-heterocyclic Pamoic acid ester ether cyano furan brominechlorine s-heterocyclic Pamoic acid ether cyano furan bromine chlorines-heterocyclic pyridine Pamoic acid iodine ketone sulfonic acid sulfatephosphate phosphonic acid carboxylic acid nitro Co-crystal FormerInteracting Group Ipriflavone ether carboxylic acid sulfate sulfonealcohol Ipriflavone pyridine cyano n-heterocyclic ketone phosphate esterfluorine Isoleucine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Isoleucine pyridine cyano n-heterocyclic ketone phosphate esterfluorine lactobionic acid pyridine cyano n-heterocyclic ketone phosphateester fluorine Lactobionic acid cyano n-heterocyclic ketone phosphateester fluorine carbamate Lactobionic acid ether carboxylic acid sulfatesulfone alcohol Lauric acid pyridine cyano n-heterocyclic ketonephosphate ester fluorine Leucine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Leucine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Lysine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Lysine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Maleic pyridine cyano n-heterocyclic ketonephosphate ester fluorine Malic Acid pyridine cyano n-heterocyclic ketonephosphate ester fluorine Malic Acid pyridine cyano n-heterocyclic ketonephosphate ester fluorine Malonic pyridine cyano n-heterocyclic ketonephosphate ester fluorine Mandelic Acid pyridine cyano n-heterocyclicketone phosphate ester fluorine Mandelic Acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine Methionine pyridine cyanon-heterocyclic ketone phosphate ester fluorine Methionine pyridine cyanon-heterocyclic ketone phosphate ester fluorine Methionine ethercarboxylic acid sulfate sulfone alcohol Nicotinamide hydroxamic acidcyano carboxamide *sulfonic acid *phosphoric acid N-oxide Nicotinamidepyridine cyano n-heterocyclic ketone phosphate ester fluorine NicotinicAcid pyridine cyano n-heterocyclic ketone phosphate ester fluorineNicotinic Acid hydroxamic acid cyano carboxamide *sulfonic acid*phosphoric acid N-oxide Orotic acid pyridine cyano n-heterocyclicketone phosphate ester fluorine Orotic acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine Oxalic acid pyridinecyano n-heterocyclic ketone phosphate ester fluorine Palmitic acidpyridine cyano n-heterocyclic ketone phosphate ester fluorine Pamoicacid pyridine cyano n-heterocyclic ketone phosphate ester fluorinePamoic acid cyano n-heterocyclic ketone phosphate ester fluorinecarbamate Pamoic acid sulfone analine Co-crystal Former InteractingGroup Ipriflavone phospphate cyanamide Ipriflavone carbamate imidazoleBF4 N—SO2 thiourea iodine Isoleucine carbamate imidazole BF4 N—SO2thiourea iodine Isoleucine carbamate imidazole BF4 N—SO2 thiourea iodinelactobionic acid carbamate imidazole BF4 N—SO2 thiourea iodineLactobionic acid imidazole BF4 Lactobionic acid phospphate cyanamideLauric acid carbamate imidazole BF4 N—SO2 thiourea iodine Leucinecarbamate imidazole BF4 N—SO2 thiourea iodine Leucine carbamateimidazole BF4 N—SO2 thiourea iodine Lysine carbamate imidazole BF4 N—SO2thiourea iodine Lysine carbamate imidazole BF4 N—SO2 thiourea iodineMaleic carbamate imidazole BF4 N—SO2 thiourea iodine Malic Acidcarbamate imidazole BF4 N—SO2 thiourea iodine epoxide Malic Acidcarbamate imidazole BF4 N—SO2 thiourea iodine Malonic carbamateimidazole BF4 N—SO2 thiourea iodine Mandelic Acid carbamate imidazoleBF4 N—SO2 thiourea iodine epoxide Mandelic Acid carbamate imidazole BF4N—SO2 thiourea iodine Methionine carbamate imidazole BF4 N—SO2 thioureaiodine Methionine carbamate imidazole BF4 N—SO2 thiourea iodineMethionine phospphate Nicotinamide ester ether fluorine acetate thionedithiadiazocyclopentadienyl Nicotinamide carbamate imidazole BF4 N—SO2thiourea iodine epoxide peroxide Nicotinic Acid carbamate imidazole BF4N—SO2 thiourea iodine Nicotinic Acid ester ether fluorine acetate thionedithiadiazocyclopentadienyl Orotic acid carbamate imidazole BF4 N—SO2thiourea iodine Orotic acid carbamate imidazole BF4 N—SO2 thioureaiodine epoxide peroxide Oxalic acid carbamate imidazole BF4 N—SO2thiourea iodine Palmitic acid carbamate imidazole BF4 N—SO2 thioureaiodine Pamoic acid carbamate imidazole BF4 N—SO2 thiourea iodine Pamoicacid imidazole BF4 Pamoic acid Co-crystal Former Co-crystal FormerFunctional Group Interacting Group Phenylalanine Amine alcohol ketonethiol amide amine analine phenol Phenylalanine Carboxylic Acid alcoholketone thiol amide amine analine phenol Piperazine Amine alcohol ketonethiol amide amine analine phenol Procaine Amine alcohol ketone thiolamide amine analine phenol Procaine Ketone alcohol thiol amide amineanaline phenol Proline Carboxylic Acid alcohol ketone thiol amide amineanaline phenol Proline Amine alcohol ketone thiol amide amine analinephenol p-Toluenesulfonic acid Sulfonic Acid pyridine ketone aldehydeether ester amide Carboxylic Acid Pyridoxamine Alcohol alcohol ketonethiol amide amine analine phenol Pyridoxamine Amine alcohol ketone thiolamide amine analine phenol Pyridoxamine Pyridine *alcohol * *amide nitro*amine *Carboxylic Acid Pyridoxine Pyridine *alcohol pyridinium * *amidenitro *amine *Carboxylic (4-Pyridoxic Acid) Acid Pyridoxine Alcoholalcohol ketone thiol amide amine analine phenol (4-Pyridoxic Acid)Pyroglutamic acid Carboxylic Acid alcohol ketone thiol amide amineanaline phenol Pyroglutamic acid Lactam alcohol ketone thiol amide amineanaline phenol Quercetin Ketone alcohol thiol amide amine analine phenolQuercetin Phenol amine amide sulfoxide n pyridine cyano aldehydeQuercetin Ether aromatic-N amide amine aromatic_s Sp2 amine sulfoxidechlorate Resveratrol Ketone alcohol thiol amide amine analine phenolResveratrol Phenol amine amide sulfoxide n pyridine cyano aldehydeSaccharin Amide alcohol ketone thiol amide amine analine phenolSaccharin Ketone alcohol thiol amide amine analine phenol SaccharinSulfoxide pyridine ketone aldehyde ether ester amide Carboxylic AcidSaccharin Amine alcohol ketone thiol amide analine phenol Salicylic AcidCarboxylic Acid alcohol ketone thiol amide amine analine phenolSalicylic Acid Alcohol alcohol ketone thiol amide amine analine phenolSalicylic Acid, 4-amino Carboxylic Acid alcohol ketone thiol amide amineanaline phenol Salicylic Acid, 4-amino alcohol alcohol ketone thiolamide amine analine phenol Salicylic Acid, 4-amino Amine alcohol ketonethiol amide amine analine phenol Co-crystal Former Interacting GroupPhenylalanine phosphate sulfate sulfone nitrate pyridine carboxilic acidmetals aldehyde Phenylalanine phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Piperazine phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Procaine phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehydeProcaine phosphate sulfate sulfone nitrate pyridine Carboxylic Acidmetals aldehyde Proline phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Proline phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde p-Toluenesulfonic acidamine metals thioether sulfate alcohol Pyridoxamine phosphate sulfatesulfone nitrate pyridine Carboxylic Acid metals aldehyde Pyridoxaminephosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Pyridoxamine *sulfonamide *ketone ether triazole ammonium oxime*chlorine Pyridoxine *sulfonamide *ketone ether triazole ammonium oxime*chlorine (4-Pyridoxic Acid) Pyridoxine phosphate sulfate sulfonenitrate pyridine Carboxylic Acid metals aldehyde (4-Pyridoxic Acid)Pyroglutamic acid phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Pyroglutamic acid phosphate sulfate sulfone nitratepyridine Carboxylic Acid metals aldehyde Quercetin phosphate sulfatesulfone nitrate pyridine Carboxylic Acid metals aldehyde Quercetinalchohol ester ether n-oxide chlorine fluorine bromine Quercetinchlorine cyano ester amine nitro nitrate bromine aldehyde Resveratrolphosphate sulfate sulfone nitrate pyridine Carboxylic Acid metalsaldehyde Resveratrol alchohol ester ether n-oxide chlorine fluorinebromine Saccharin phosphate sulfate sulfone nitrate pyridine CarboxylicAcid metals aldehyde Saccharin phosphate sulfate sulfone nitratepyridine Carboxylic Acid metals aldehyde Saccharin amine metalsthioether sulfate alcohol Saccharin phosphate sulfate sulfone nitratepyridine Carboxylic Acid metals aldehyde Salicylic Acid phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehydeSalicylic Acid phosphate sulfate sulfone nitrate pyridine CarboxylicAcid metals aldehyde Salicylic Acid, 4-amino phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Salicylic Acid, 4-aminophosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde ester Salicylic Acid, 4-amino phosphate sulfate sulfone nitratepyridine carboxilic acid metals aldehyde Co-crystal Former InteractingGroup Phenylalanine ester ether cyano furan bromine chlorines-heterocyclic Phenylalanine ester ether cyano furan bromine chlorines-heterocyclic Piperazine ester ether cyano furan bromine chlorines-heterocyclic Procaine ester ether cyano furan bromine chlorines-heterocyclic Procaine ester ether cyano furan bromine chlorines-heterocyclic Proline ester ether cyano furan bromine chlorines-heterocyclic Proline ester ether cyano furan bromine chlorines-heterocyclic p-Toluenesulfonic acid Pyridoxamine ester ether cyanofuran bromine chlorine s-heterocyclic Pyridoxamine ester ether cyanofuran bromine chlorine s-heterocyclic Pyridoxamine thiol n-heterocyclicthionedisulfide iodine hydrazone thiocyanate *bromine ring Pyridoxinethiol n-heterocyclic thionedisulfide pyrrolidindione iodine hydrazonethiocyanate *bromine (4-Pyridoxic Acid) ring Pyridoxine ester ethercyano furan bromine chlorine s-heterocyclic (4-Pyridoxic Acid)Pyroglutamic acid ester ether cyano furan bromine chlorines-heterocyclic Pyroglutamic acid ester ether cyano furan brominechlorine s-heterocyclic Quercetin ester ether cyano furan brominechlorine s-heterocyclic Quercetin iodine ketone sulfonic acid sulfatephosphate phosphonic acid carboxylic acid nitro Quercetin ketoneperoxide epoxide heterocyclic-S iodine ester Resveratrol ester ethercyano furan bromine chlorine s-heterocyclic Resveratrol iodine ketonesulfonic acid sulfate phosphate phosphonic acid carboxylic acid nitroSaccharin ester ether cyano furan bromine chlorine s-heterocyclicSaccharin ester ether cyano furan bromine chlorine s-heterocyclicSaccharin Saccharin ester ether cyano furan bromine chlorines-heterocyclic Salicylic Acid ester ether cyano furan bromine chlorines-heterocyclic Salicylic Acid ester ether cyano furan bromine chlorines-heterocyclic Salicylic Acid, 4-amino ester ether cyano furan brominechlorine s-heterocyclic Salicylic Acid, 4-amino ether cyano furanbromine chlorine s-heterocyclic pyridine Salicylic Acid, 4-amino esterether cyano furan bromine chlorine s-heterocyclic Co-crystal FormerInteracting Group Phenylalanine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Phenylalanine pyridine cyano n-heterocyclicketone phosphate ester fluorine Piperazine pyridine cyano n-heterocyclicketone phosphate ester fluorine Procaine pyridine cyano n-heterocyclicketone phosphate ester fluorine Procaine pyridine cyano n-heterocyclicketone phosphate ester fluorine Proline pyridine cyano n-heterocyclicketone phosphate ester fluorine Proline pyridine cyano n-heterocyclicketone phosphate ester fluorine p-Toluenesulfonic acid Pyridoxaminepyridine cyano n-heterocyclic ketone phosphate ester fluorinePyridoxamine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Pyridoxamine hydroxamic acid cyano carboxamide *sulfonic acid*phosphoric acid N-oxide Pyridoxine hydroxamic acid cyano carboxamide*sulfonic acid *phosphoric acid N-oxide (4-Pyridoxic Acid) Pyridoxinepyridine cyano n-heterocyclic ketone phosphate ester fluorine(4-Pyridoxic Acid) Pyroglutamic acid pyridine cyano n-heterocyclicketone phosphate ester fluorine Pyroglutamic acid pyridine cyanon-heterocyclic ketone phosphate ester fluorine Quercetin pyridine cyanon-heterocyclic ketone phosphate ester fluorine Quercetin sulfone analineQuercetin ether carboxylic acid sulfate sulfone alcohol Resveratrolpyridine cyano n-heterocyclic ketone phosphate ester fluorineResveratrol sulfone analine Saccharin pyridine cyano n-heterocyclicketone phosphate ester fluorine Saccharin pyridine cyano n-heterocyclicketone phosphate ester fluorine Saccharin Saccharin pyridine cyanon-heterocyclic ketone phosphate ester fluorine Salicylic Acid pyridinecyano n-heterocyclic ketone phosphate ester fluorine Salicylic Acidpyridine cyano n-heterocyclic ketone phosphate ester fluorine SalicylicAcid, 4-amino pyridine cyano n-heterocyclic ketone phosphate esterfluorine Salicylic Acid, 4-amino cyano n-heterocyclic ketone phosphateester fluorine carbamate Salicylic Acid, 4-amino pyridine cyanon-heterocyclic ketone phosphate ester fluorine Co-crystal FormerInteracting Group Phenylalanine carbamate imidazole BF4 N—SO2 thioureaiodine Phenylalanine carbamate imidazole BF4 N—SO2 thiourea iodinePiperazine carbamate imidazole BF4 N—SO2 thiourea iodine Procainecarbamate imidazole BF4 N—SO2 thiourea iodine Procaine carbamateimidazole BF4 N—SO2 thiourea iodine Proline carbamate imidazole BF4N—SO2 thiourea iodine Proline carbamate imidazole BF4 N—SO2 thioureaiodine p-Toluenesulfonic acid Pyridoxamine carbamate imidazole BF4 N—SO2thiourea iodine epoxide Pyridoxamine carbamate imidazole BF4 N—SO2thiourea iodine Pyridoxamine ester ether fluorine acetate thionedithiadiazocyclopentadienyl Pyridoxine ester ether fluorine acetatethione dithiadiazocyclopentadienyl (4-Pyridoxic Acid) Pyridoxinecarbamate imidazole BF4 N—SO2 thiourea iodine epoxide (4-Pyridoxic Acid)Pyroglutamic acid carbamate imidazole BF4 N—SO2 thiourea iodinePyroglutamic acid carbamate imidazole BF4 N—SO2 thiourea iodine epoxideperoxide Quercetin carbamate imidazole BF4 N—SO2 thiourea iodineQuercetin Quercetin phospphate cyanamide Resveratrol carbamate imidazoleBF4 N—SO2 thiourea iodine Resveratrol Saccharin carbamate imidazole BF4N—SO2 thiourea iodine epoxide peroxide Saccharin carbamate imidazole BF4N—SO2 thiourea iodine Saccharin Saccharin carbamate imidazole BF4 N—SO2thiourea iodine Salicylic Acid carbamate imidazole BF4 N—SO2 thioureaiodine Salicylic Acid carbamate imidazole BF4 N—SO2 thiourea iodineepoxide Salicylic Acid, 4-amino carbamate imidazole BF4 N—SO2 thioureaiodine Salicylic Acid, 4-amino imidazole BF4 Salicylic Acid, 4-aminocarbamate imidazole BF4 N—SO2 thiourea iodine Co-crystal FormerCo-crystal Former Functional Group Interacting Group Sebacic acidCarboxylic Acid alcohol ketone thiol amide amine analine phenol SerineCarboxylic Acid alcohol ketone thiol amide amine analine phenol SerineAmine alcohol ketone thiol amide amine analine phenol Serine Alcoholalcohol ketone thiol amide amine analine phenol Stearic acid CarboxylicAcid alcohol ketone thiol amide amine analine phenol Succinic AcidCarboxylic Acid alcohol ketone thiol amide amine analine phenol TartaricAcid Carboxylic Acid alcohol ketone thiol amide amine analine phenolThreonine Amine alcohol ketone thiol amide amine analine phenolThreonine Carboxylic Acid alcohol ketone thiol amide amine analinephenol Threonine alcohol alcohol ketone thiol amide amine analine phenolTris Amine alcohol ketone thiol amide amine analine phenol Tris Alcoholalcohol ketone thiol amide amine analine phenol Tryptophan Amine alcoholketone thiol amide amine analine phenol Tryptophan Carboxylic Acidalcohol ketone thiol amide amine analine phenol Tryptophan Indole*alcohol pyridinium * *amide nitro *amine *carboxilic acid TyrosineAmine alcohol ketone thiol amide amine analine phenol TyrosineCarboxylic Acid alcohol ketone thiol amide amine analine phenol TyrosineAlcohol alcohol ketone thiol amide amine analine phenol Urea Ketonealcohol thiol amide amine analine phenol Urea Amine alcohol ketone thiolamide amine analine phenol Urea Amide alcohol ketone thiol amide amineanaline phenol Valine Amine alcohol ketone thiol amide amine analinephenol Valine Carboxylic Acid alcohol ketone thiol amide amine analinephenol Vitamin K5 Amine alcohol ketone thiol amide amine analine phenolVitamin K5 Alcohol alcohol ketone thiol amide amine analine phenolXylitol Alcohol alcohol ketone thiol amide amine analine phenolCo-crystal Former Interacting Group Sebacic acid phosphate sulfatesulfone nitrate pyridine carboxilic acid metals aldehyde Serinephosphate sulfate sulfone nitrate pyridine Carboxylic Acid metalsaldehyde Serine phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Serine phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde Stearic acid phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Succinic Acid phosphatesulfate sulfone nitrate pyridine Carboxylic Acid metals aldehydeTartaric Acid phosphate sulfate sulfone nitrate pyridine Carboxylic Acidmetals aldehyde Threonine phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Threonine phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Threonine phosphatesulfate sulfone nitrate pyridine Carboxylic Acid metals aldehyde Trisphosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Tris phosphate sulfate sulfone nitrate pyridine Carboxylic Acidmetals aldehyde Tryptophan phosphate sulfate sulfone nitrate pyridinecarboxilic acid metals aldehyde Tryptophan phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Tryptophan *sulfonamide*ketone ether triazole ammonium oxime *chlorine Tyrosine phosphatesulfate sulfone nitrate pyridine carboxilic acid metals aldehydeTyrosine phosphate sulfate sulfone nitrate pyridine carboxilic acidmetals aldehyde Tyrosine phosphate sulfate sulfone nitrate pyridineCarboxylic Acid metals aldehyde Urea phosphate sulfate sulfone nitratepyridine Carboxylic Acid metals aldehyde Urea phosphate sulfate sulfonenitrate pyridine carboxilic acid metals aldehyde Urea phosphate sulfatesulfone nitrate pyridine Carboxylic Acid metals aldehyde Valinephosphate sulfate sulfone nitrate pyridine carboxilic acid metalsaldehyde Valine phosphate sulfate sulfone nitrate pyridine carboxilicacid metals aldehyde Vitamin K5 phosphate sulfate sulfone nitratepyridine carboxilic acid metals aldehyde Vitamin K5 phosphate sulfatesulfone nitrate pyridine Carboxylic Acid metals aldehyde Xylitolphosphate sulfate sulfone nitrate pyridine Carboxylic Acid metalsaldehyde Co-crystal Former Interacting Group Sebacic acid ester ethercyano furan bromine chlorine s-heterocyclic Serine ester ether cyanofuran bromine chlorine s-heterocyclic Serine ester ether cyano furanbromine chlorine s-heterocyclic Serine ester ether cyano furan brominechlorine s-heterocyclic Stearic acid ester ether cyano furan brominechlorine s-heterocyclic Succinic Acid ester ether cyano furan brominechlorine s-heterocyclic Tartaric Acid ester ether cyano furan brominechlorine s-heterocyclic Threonine ester ether cyano furan brominechlorine s-heterocyclic Threonine ester ether cyano furan brominechlorine s-heterocyclic Threonine ester ether cyano furan brominechlorine s-heterocyclic Tris ester ether cyano furan bromine chlorines-heterocyclic Tris ester ether cyano furan bromine chlorines-heterocyclic Tryptophan ester ether cyano furan bromine chlorines-heterocyclic Tryptophan ester ether cyano furan bromine chlorines-heterocyclic Tryptophan thiol n-heterocyclic thionedisulfidepyrrolidindione iodine hydrazone thiocyanate *bromine ring Tyrosineester ether cyano furan bromine chlorine s-heterocyclic Tyrosine esterether cyano furan bromine chlorine s-heterocyclic Tyrosine ester ethercyano furan bromine chlorine s-heterocyclic Urea ester ether cyano furanbromine chlorine s-heterocyclic Urea ester ether cyano furan brominechlorine s-heterocyclic Urea ester ether cyano furan bromine chlorines-heterocyclic Valine ester ether cyano furan bromine chlorines-heterocyclic Valine ester ether cyano furan bromine chlorines-heterocyclic Vitamin K5 ester ether cyano furan bromine chlorines-heterocyclic Vitamin K5 ester ether cyano furan bromine chlorines-heterocyclic Xylitol ester ether cyano furan bromine chlorines-heterocyclic Co-crystal Former Interacting Group Sebacic acid pyridinecyano n-heterocyclic ketone phosphate ester fluorine Serine pyridinecyano n-heterocyclic ketone phosphate ester fluorine Serine pyridinecyano n-heterocyclic ketone phosphate ester fluorine Serine pyridinecyano n-heterocyclic ketone phosphate ester fluorine Stearic acidpyridine cyano n-heterocyclic ketone phosphate ester fluorine SuccinicAcid pyridine cyano n-heterocyclic ketone phosphate ester fluorineTartaric Acid pyridine cyano n-heterocyclic ketone phosphate esterfluorine Threonine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Threonine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Threonine pyridine cyano n-heterocyclic ketone phosphate esterfluorine Tris pyridine cyano n-heterocyclic ketone phosphate esterfluorine Tris pyridine cyano n-heterocyclic ketone phosphate esterfluorine Tryptophan pyridine cyano n-heterocyclic ketone phosphate esterfluorine Tryptophan pyridine cyano n-heterocyclic ketone phosphate esterfluorine Tryptophan hydroxamic acid cyano carboxamide *sulfonic acid*phosphoric acid N-oxide Tyrosine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Tyrosine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Tyrosine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Urea pyridine cyano n-heterocyclic ketonephosphate ester fluorine Urea pyridine cyano n-heterocyclic ketonephosphate ester fluorine Urea pyridine cyano n-heterocyclic ketonephosphate ester fluorine Valine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Valine pyridine cyano n-heterocyclic ketonephosphate ester fluorine Vitamin K5 pyridine cyano n-heterocyclic ketonephosphate ester fluorine Vitamin K5 pyridine cyano n-heterocyclic ketonephosphate ester fluorine Xylitol pyridine cyano n-heterocyclic ketonephosphate ester fluorine Co-crystal Former Interacting Group Sebacicacid carbamate imidazole BF4 N—SO2 thiourea iodine Serine carbamateimidazole BF4 N—SO2 thiourea iodine Serine carbamate imidazole BF4 N—SO2thiourea iodine Serine carbamate imidazole BF4 N—SO2 thiourea iodineepoxide Stearic acid carbamate imidazole BF4 N—SO2 thiourea iodineSuccinic Acid carbamate imidazole BF4 N—SO2 thiourea iodine TartaricAcid carbamate imidazole BF4 N—SO2 thiourea iodine Threonine carbamateimidazole BF4 N—SO2 thiourea iodine Threonine carbamate imidazole BF4N—SO2 thiourea iodine Threonine carbamate imidazole BF4 N—SO2 thioureaiodine epoxide Tris carbamate imidazole BF4 N—SO2 thiourea iodine Triscarbamate imidazole BF4 N—SO2 thiourea iodine epoxide Tryptophancarbamate imidazole BF4 N—SO2 thiourea iodine Tryptophan carbamateimidazole BF4 N—SO2 thiourea iodine Tryptophan ester ether fluorineacetate thione dithiadiazocyclopentadienyl Tyrosine carbamate imidazoleBF4 N—SO2 thiourea iodine Tyrosine carbamate imidazole BF4 N—SO2thiourea iodine Tyrosine carbamate imidazole BF4 N—SO2 thiourea iodineepoxide Urea carbamate imidazole BF4 N—SO2 thiourea iodine Ureacarbamate imidazole BF4 N—SO2 thiourea iodine Urea carbamate imidazoleBF4 N—SO2 thiourea iodine epoxide peroxide Valine carbamate imidazoleBF4 N—SO2 thiourea iodine Valine carbamate imidazole BF4 N—SO2 thioureaiodine Vitamin K5 carbamate imidazole BF4 N—SO2 thiourea iodine VitaminK5 carbamate imidazole BF4 N—SO2 thiourea iodine epoxide Xylitolcarbamate imidazole BF4 N—SO2 thiourea iodine epoxide

TABLE III Functional Functional Group Group Structure Interacting Grouppyridine

*alcohol pyridinium *amide nitro *amine *carboxilic acid imidazole

imidazole chlorine acetamide carboxylate thione nitro Hydroxamic acid

hydroxamic acid alcohol phosphinic ester alkane pyridine amide peroxideR—O—OH ester peroxide amide ether alkane N-heterocycle epoxide

alkane bromine alcohol ester epoxide amide thioester

aromatic thioester alkane sulfamide hydroxy bromine thioketone

alkane thioketone ketone SULFAMIDE AMINE thiol Functional Group pyridine*sulfonamide *ketone ether triazole alkane ammonium oxime *chlorinealkyne thiol imidazole cyanamide ketone cyano carboxilic alcohol alkanethiol amine phosphinic chlorine acid acid hemi- hydrate Hydroxamicsulfonamide carboxylate phosphine amine aromatic acid peroxide aromaticalcohol pyrimid- analine thiazole peroxy acid ketone carboxilic azidephosphine inedione acid oxide epoxide alkene hydrazone aromaticthioether ketone aldehyde chlorine carboxilic alkyne acid thioesteriodine amine cyano thioketone amide chlorine nitro thioketone sulfoxideoxo chlorine bromine AROMATIC alkene sulfone iodine AZOXY potassiumpyridine n-heterocyclic thionedisulfide pyrroli- iodine hydrazonethiocyanate *bromine aromatic hydrox- cyano ring dindione amic acidimidazole sulfonyl sulfoxide amide fluorine sulfonate ester Hydroxamicacid peroxide sulfonamide analine epoxide ammonium fluorine nitro aminecyano thioester thioketone epoxide n-oxide cyano iron cobalt aminesulfate pyridine carboxamide *sulfonic *phosphoric N-oxide ester etherfluorine acetate thione dithiadi- acid acid azocyclo penta- dienylimidazole Hydroxamic acid peroxide epoxide thioester thioketone pyridineimidazole Hydroxamic acid peroxide epoxide thioester thioketoneFunctional Functional Group Group Structure Interacting Group nitrateester

aromatic amide alkane chlorine nitrate ester bromine Thiophosphateester-O

amine imidazole cyclic amide Phosphate ester

aromatic alcohol phosphate ester aromatic N- ring pyridine analineKetone

alcohol ketone thiol amide amine analine Aldehyde

alcohol ketone thiol amide amine analine Thiol R—SH carboxylic acidsodium aldehyde ketone aromatic-N cadmium Alcohol R—OH alcohol ketonethiol amide amine analine Functional Group nitrate ester alcohol etheracetate Thio- phosphate ester-O Phosphate amine sodium potassium lithiumcarboxylic amide alkane ester acid Ketone phenol phosphate sulfatesulfone nitrate pyridine aromatic carboxilic metals aldehyde acidAldehyde phenol phosphate sulfate sulfone nitrate pyridine aromaticcarboxilic metals aldehyde acid Thiol alkane arsenic chlorine alcoholpotassium Ru aromatic Rb Sb Alcohol phenol phosphate sulfate sulfonenitrate pyridine aromatic carboxilic metals aldehyde acid nitrate esterThio- phosphate ester-O Phosphate ester Ketone ester ether cyano furanbromine chlorine s-hetero- pyridine cyano cyclic Aldehyde ester ethercyano furan bromine chlorine s-hetero- pyridine cyano cyclic ThiolAlcohol ester ether cyano furan bromine chlorine s-hetero- pyridinecyano cyclic Functional Group nitrate ester Thio- phosphate ester-OPhosphate ester Ketone n-heterocyclic ketone phosphate fluorinecarbamate imidazole BF4 alkane aromatic N-SO2 ester Aldehyden-heteracyclic ketone phosphate fluorine carbamate imidazole BF4 alkanearomatic N-SO2 ester Thiol Alcohol n-heterocyclic ketone phosphatefluorine carbamate imidazole BF4 alkane aromatic N-SO2 ester FunctionalGroup nitrate ester Thio- phosphate ester-O Phosphate ester Ketonethiourea iodine Aldehyde thiourea iodine epoxide Thiol Alcohol thioureaiodine epoxide Functional Functional Group Group Structure InteractingGroup Thioether

aromatic-N amide amine aromatic_s Sp2 amine sulfoxide Ether

aromatic-N amide amine aromatic_s Sp2 amine sulfoxide Cyanamide

cyano amine potassium aromatic-N bromine sodium Thiocyanate

aromatic-S ester ether sP2 amine

thioether ether metals MoOCl4 BF4 bromine Amine primary R—NH₂ alcoholketone thiol amide amine analine Amine secondary R—NH alcohol ketonethiol amide amine analine Functional Group Thiosther chlorate chlorinealkyne cyano ester amine nitro nitrate bromine aldehyde Ether chloratechlorine alkyne cyano ester amine nitro nitrate bromine aldehydeCyanamide imidazole ether n-hetero- alcohol cesium Ag cyclic ThiocyanatesP2 amine chlorine Sp2 amine sulfate Osmium Amine phenol phosphatesulfate sulfone nitrate pyridine aromatic carboxilic metals aldehydeprimary acid Amine phenol phosphate sulfate sulfone nitrate pyridinearomatic carboxilic metals aldehyde secondary acid Thioether ketoneperoxide epoxide Ag Se hetero- iodine ester ether carboxylic cyclic-Sacid Ether ketone peroxide epoxide Ag Se hetero iodine ester ethercarboxylic cyclic-S acid Cyanamide Thiocyanate sP2 amine Amine esterether cyano furan bromine chlorine s-hetero- pyridine cyano primarycyclic Amine ester ether cyano furan bromine chlorine s-hetero- pyridinecyano secondary cyclic Functional Group Thioether sulfate sulfone alkaneal- phospphate co- hol Ether sulfate sulfone alkane al- phospphatecyanamide co- hol Cyanamide Thiocyanate sP2 amine Amine n-heterocyclicketone phosphate fluorine carbamate imidazole BF4 alkane aromatic N-SO2primary ester Amine n-heterocyclic ketone phosphate fluorine carbamateimidazole BF4 alkane aromatic N-SO2 secondary ester Thioether EtherCyanamide Thiocyanate sP2 amine Amine thiourea iodine primary Aminethiourea iodine secondary Functional Functional Group Group StructureInteracting Group Amine tertiary R₃—N alcohol ketone thiol amide amineanaline Amide

alcohol ketone thiol amide amine analine Sulfonic acid

pyridine ketone aldehyde ether ester amide Phosphinic acid

alkane potassium lithium n-heterocyclic oxime amide Phosphonic acid

alkane potassium lithium n-heterocyclic oxime amide Carboxylic acid

alcohol ketone thiol amide amine analine Functional Group Amine phenolphosphate sulfate sulfone nitrate pyridine aromatic carboxilic metalsaldehyde tertiary acid Amide phenol phosphate sulfate sulfone nitratepyridine aromatic carboxilic metals aldehyde acid Sulfonic acidcarboxilic acid amine metals thioether sulfate alcohol Phosphinic phenolaromatic amine alcohol metals acid Phosphonic phenol aromatic aminealcohol metals carboxylic Sp2 amine analine ether acid acid Carboxylicphenol phosphate sulfate sulfone nitrate pyridine aromatic carboxilicmetals aldehyde acid acid Amine ester ether cyano furan bromine chlorines-hetero- pyridine cyano tertiary cyclic Amide ester ether cyano furanbromine chlorine s-hetero- pyridine cyano cyclic Sulfonic acidPhosphinic acid Phosphonic phosphonic aromatic-N ketone aldehydeimidazole acid acid Carboxylic ester ether cyano furan bromine chlorines-hetero- pyridine cyano acid cyclic Functional Group Aminen-heterocyclic ketone phosphate fluorine carbamate imidazole BF4 alkanearomatic N-SO2 tertiary ester Amide n-heterocyclic ketone phosphatefluorine carbamate imidazole BF4 alkane aromatic N-SO2 ester Sulfonicacid Phosphinic acid Phosphonic acid Carboxylic n-heterocyclic ketonephosphate fluorine carbamate imidazole BF4 alkane aromatic N-SO2 acidester Functional Group Amine thiourea iodine tertiary Amide thioureaiodine epoxide peroxide Sulfonic acid Phosphinic acid Phosphonic acidCarboxylic thiourea iodine acid Functional Functional Group GroupStructure Interacting Group Sulfate ester

pyridine ketone aldehyde ether ester amide Oxime C═N—OH alcohol alkaneamine amide ether ester Nitrile

metal ketone phenol alcohol cyano Diazo RH₂C—N═N—CH₂R Oxime Nitro NO₂pyridine ketone aldehyde ether ester amide S-hetorocyclic ring

alcohol thioketone thioether s-heterocyclic ketone aromatic Thiophene

chlorine fluorine amide ketone NO SO Functional Group Sulfate estercarboxilic acid amine metals thioether sulfate alcohol Oxime pyridinen-aromatic chlorate chlorine Sp2-N diazo thioketone cyano n-oxide ketoneNitrile amine analine bromine amide alkane carboxylic chlorine n-hetero-aromatic potassium acid cyclic Diazo Nitro carboxilic acid amine metalsthioether sulfate alcohol S-hetero- alkene amine chlorine BF4 sulfateester NO ether amide iodine cyclic ring Thiophene CO Sulfate ester Oximealdehyde carboxylic acid bromine aromatic pyridine BF4 Nitrile aldehydethioether pyridine n-aromatic bromine ether s-aromatic thiophene DiazoNitro S-hetero- carboxylic acid sodium cyano chloride furan cyclic ringThiophene Sulfate ester Oxime Nitrile Diazo Nitro S-hetero- cyclic ringThiophene Sulfate ester Oxime Nitrile Diazo Nitro S-hetero- cyclic ringThiophene Functional Functional Group Group Structure Interacting GroupN-hetero- cyclic ring

alcohol thioketone thioether s-heterocyclic ketone aromatic O-hetero-cyclic ring

alcohol thioketone thioether s-heterocyclic ketone aromatic Pyrrole

chlorine fluorine amide ketone NO SO Furan

s-heterocyclic Functional Group N-hetero- alkene amine chlorine BF4sulfate ester NO ether amide iodine cyclic ring O-hetero- alkene aminechlorine BF4 sulfate ester NO ether amide iodine cyclic ring Pyrrole COimidazole pyridine n-aromatic aldehyde carboxylic sulfate chlorinebromine oxime acid Furan N-hetero- carboxylic acid sodium cyano chloridealdehyde cyclic ring O-hetero- carboxylic acid sodium cyano chloridealdehyde cyclic ring Pyrrole alcohol phenol ester ether Furan N-hetero-cyclic ring O-hetero- cyclic ring Pyrrole Furan N-hetero- cyclic ringO-hetero- cyclic ring Pyrrole Furan

1. A co-crystal composition, comprising: modafinil and a co-crystalformer, wherein the co-crystal former is a solid at room temperature,and wherein the modafinil and the co-crystal former are hydrogen bondedto each other.
 2. The co-crystal composition according to claim 1,wherein: (a) the co-crystal former is selected from a co-crystal formerof Table I or Table II; (b) the co-crystal former has at least onefunctional group selected from the group consisting of ether, thioether,alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphateester, thiophosphate ester, ester, thioester, sulfate ester, carboxylicacid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primaryamine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate,cyanamide, oxime, nitrile diazo, organohalide, nitro, S-heterocyclicring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring,furan, epoxide, hydroxamic acid, imidazole, and pyridine; (c) thesolubility of the co-crystal is increased as compared to the modafinil;(d) the dose response of the co-crystal is increased as compared to themodafinil; (e) the dissolution of the co-crystal is increased ascompared to the modafinil; (f) the bioavailability of the co-crystal isincreased as compared to the modafinil; or (g) the stability of theco-crystal is increased as compared to the modafinil.
 3. A co-crystalcomposition, comprising: modafinil, a co-crystal former, and a thirdmolecule; wherein the co-crystal former is a solid at room temperature,and wherein the modafinil and the third molecule are bonded to eachother, and further wherein the co-crystal former and the third moleculeare hydrogen bonded to each other.
 4. The co-crystal compositionaccording to claim 3, wherein: (a) the co-crystal former is selectedfrom a co-crystal former of Table I or Table II; (b) the co-crystalformer has at least one functional group selected from the groupconsisting of ether, thioether, alcohol, thiol, aldehyde, ketone,thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester,thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinicacid, sulfonic acid, amide, primary amine, secondary amine, ammonia,tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile diazo,organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclicring, pyrrole, O-heterocyclic ring, furan, epoxide, hydroxamic acid,imidazole, and pyridine; or (c) the solubility of the co-crystal isincreased as compared to the modafinil; (d) the dose response of theco-crystal is increased as compared to the modafinil; (e) thedissolution of the co-crystal is increased as compared to the modafinil;(f) the bioavailability of the co-crystal is increased as compared tothe modafinil; or (g) the stability of the co-crystal is increased ascompared to the modafinil.
 5. A co-crystal composition, comprising:modafinil and a second API, wherein the second API is either a liquid ora solid at room temperature, and wherein the modafinil and the secondAPI are hydrogen bonded to a molecule.
 6. The co-crystal compositionaccording to claim 5, wherein: (a) the modafinil is hydrogen bonded tothe second API; (b) the second API is a liquid at room temperature; (c)the second API is a solid at room temperature; (d) the second API has atleast one functional group selected from the group consisting of ether,thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester,phosphate ester, thiophosphate ester, ester, thioester, sulfate ester,carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide,primary amine, secondary amine, ammonia, tertiary amine, sp2 amine,thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro,S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole,O-heterocyclic ring, furan, epoxide, hydroxamic acid, imidazole, andpyridine; (e) the solubility of the co-crystal is increased as comparedto the modafinil; (f) the dose response of the co-crystal is increasedas compared to the modafinil; (g) the dissolution of the co-crystal isincreased as compared to the modafinil; (h) the bioavailability of theco-crystal is increased as compared to the modafinil; or (i) thestability of the co-crystal is increased as compared to the modafinil.7. (canceled)
 8. A co-crystal comprising modafinil and a co-crystalformer selected from the group consisting of: malonic acid, glycolicacid, fumaric acid, tartaric acid, citric acid, succinic acid, gentisicacid, oxalic acid, 1-hydroxy-2-naphthoic acid, orotic acid, glutaricacid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauricacid, L-malic acid, and maleic acid.
 9. The co-crystal according toclaim 8, wherein: (a) the co-crystal is characterized by a powder X-raydiffraction pattern comprising peaks expressed in terms of 2-thetaangles, wherein: (i) said co-crystal is a modafinil:malonic acidco-crystal and said X-ray diffraction pattern comprises peaks at 5.08,9.28, and 16.81 degrees; (ii) said co-crystal is a modafinil:malonicacid co-crystal and said X-ray diffraction pattern comprises peaks at16.81, 18.27, and 19.45 degrees; (iii) said co-crystal is amodafinil:malonic acid co-crystal and said X-ray diffraction patterncomprises peaks at 9.28, 19.45, and 22.83 degrees; (iv) said co-crystalis a modafinil:malonic acid co-crystal and said X-ray diffractionpattern comprises peaks at 5.08 and 9.28 degrees; (v) said co-crystal isa modafinil:malonic acid co-crystal and said X-ray diffraction patterncomprises peaks at 16.81 and 19.45 degrees; (vi) said co-crystal is amodafinil:malonic acid co-crystal and said X-ray diffraction patterncomprises peaks at 18.27 and 22.83 degrees; (vii) said co-crystal is amodafinil:malonic acid co-crystal and said X-ray diffraction patterncomprises a peak at 5.08 degrees; (viii) said co-crystal is amodafinil:malonic acid co-crystal and said X-ray diffraction patterncomprises a peak at 9.28 degrees; or (ix) said co-crystal is amodafinil:malonic acid co-crystal and said X-ray diffraction patterncomprises a peak at 16.81 degrees; (b) the co-crystal is characterizedby a DSC thermogram, wherein said co-crystal is a modafinil:malonic acidco-crystal and said DSC thermogram comprises an endothermic transitionat about 116 degrees C.; or (c) the co-crystal is characterized by aRaman spectrum comprising peaks expressed in terms of cm⁻¹, wherein: (i)said co-crystal is a modafinil:malonic acid co-crystal and said Ramanspectrum comprises peaks at 1004, 633, and 265; (ii) said co-crystal isa modafinil:malonic acid co-crystal and said Raman spectrum comprisespeaks at 1032, 1601, and 767; (iii) said co-crystal is amodafinil:malonic acid co-crystal and said Raman spectrum comprisespeaks at 1004 and 633; (iv) said co-crystal is a modafinil:malonic acidco-crystal and said Raman spectrum comprises peaks at 1183 and 767; or(v) said co-crystal is a modafinil:malonic acid co-crystal and saidRaman spectrum comprises peaks at 1601 and
 718. 10. The co-crystalaccording to claim 8, wherein the co-crystal is characterized by apowder X-ray diffraction pattern comprising peaks expressed in terms of2-theta angles, wherein: (a) said co-crystal is a modafinil:glycolicacid co-crystal and said X-ray diffraction pattern comprises peaks at9.51, 15.97, and 20.03 degrees; (b) said co-crystal is amodafinil:glycolic acid co-crystal and said X-ray diffraction patterncomprises peaks at 14.91, 19.01, and 22.75 degrees; (c) said co-crystalis a modafinil:glycolic acid co-crystal and said X-ray diffractionpattern comprises peaks at 15.97, 25.03, and 25.71 degrees; (d) saidco-crystal is a modafinil:glycolic acid co-crystal and said X-raydiffraction pattern comprises peaks at 9.51 and 15.97 degrees; (e) saidco-crystal is a modafinil:glycolic acid co-crystal and said X-raydiffraction pattern comprises peaks at 20.03 and 25.03 degrees; (f) saidco-crystal is a modafinil:glycolic acid co-crystal and said X-raydiffraction pattern comprises peaks at 15.97 and 25.03 degrees; (g) saidco-crystal is a modafinil:glycolic acid co-crystal and said X-raydiffraction pattern comprises a peak at 9.51 degrees; (h) saidco-crystal is a modafinil:glycolic acid co-crystal and said X-raydiffraction pattern comprises a peak at 15.97 degrees; or (i) saidco-crystal is a modafinil:glycolic acid co-crystal and said X-raydiffraction pattern comprises a peak at 20.03 degrees.
 11. Theco-crystal according to claim 8, wherein: (a) the co-crystal ischaracterized by a powder X-ray diffraction pattern comprising peaksexpressed in terms of 2-theta angles, wherein: (i) said co-crystal is amodafinil:maleic acid co-crystal and said X-ray diffraction patterncomprises peaks at 4.69, 6.15, and 9.61 degrees; (ii) said co-crystal isa modafinil:maleic acid co-crystal and said X-ray diffraction patterncomprises peaks at 10.23, 19.97, and 21.83 degrees; (iii) saidco-crystal is a modafinil:maleic acid co-crystal and said X-raydiffraction pattern comprises peaks at 4.69, 10.23, and 21.83 degrees;(iv) said co-crystal is a modafinil:maleic acid co-crystal and saidX-ray diffraction pattern comprises peaks at 4.69 and 19.97 degrees; (v)said co-crystal is a modafinil:maleic acid co-crystal and said X-raydiffraction pattern comprises peaks at 6.15 and 9.61 degrees; (vi) saidco-crystal is a modafinil:maleic acid co-crystal and said X-raydiffraction pattern comprises peaks at 4.69 and 6.15 degrees; (vii) saidco-crystal is a modafinil:maleic acid co-crystal and said X-raydiffraction pattern comprises a peak at 4.69 degrees; (viii) saidco-crystal is a modafinil:maleic acid co-crystal and said X-raydiffraction pattern comprises a peak at 9.61 degrees; or (x) saidco-crystal is a modafinil:maleic acid co-crystal and said X-raydiffraction pattern comprises a peak at 19.97 degrees; or (b) theco-crystal is characterized by a DSC thermogram, wherein said co-crystalis a modafinil:maleic acid co-crystal and said DSC thermogram comprisesan endothermic transition at about 168 degrees C.
 12. The co-crystalaccording to claim 8, wherein the co-crystal is characterized by apowder X-ray diffraction pattern comprising peaks expressed in terms of2-theta angles, wherein: (a) said co-crystal is a modafinil:L-tartaricacid co-crystal and said X-ray diffraction pattern comprises peaks at6.10, 14.33, and 20.71 degrees; (b) said co-crystal is amodafinil:L-tartaric acid co-crystal and said X-ray diffraction patterncomprises peaks at 16.93, 20.15, and 22.49 degrees; (c) said co-crystalis a modafinil:L-tartaric acid co-crystal and said X-ray diffractionpattern comprises peaks at 16.93, 20.71, and 29.72 degrees; (d) saidco-crystal is a modafinil:L-tartaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 6.10 and 20.15 degrees; (e) saidco-crystal is a modafinil:L-tartaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 14.33 and 20.71 degrees; (f) saidco-crystal is a modafinil:L-tartaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 7.36 and 25.04 degrees; (g) saidco-crystal is a modafinil:L-tartaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 6.10 degrees; (h) saidco-crystal is a modafinil:L-tartaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 16.93 degrees; or (i) saidco-crystal is a modafinil:L-tartaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 20.71 degrees.
 13. Theco-crystal according to claim 8, wherein the co-crystal is characterizedby a powder X-ray diffraction pattern comprising peaks expressed interms of 2-theta angles, wherein: (a) said co-crystal is amodafinil:citric acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.29, 7.29, and 9.31 degrees; (b) said co-crystal isa modafinil:citric acid co-crystal and said X-ray diffraction patterncomprises peaks at 12.41, 13.29, and 14.61 degrees; (c) said co-crystalis a modafinil:citric acid co-crystal and said X-ray diffraction patterncomprises peaks at 17.29, 17.97, and 21.37 degrees; (d) said co-crystalis a modafinil:citric acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.29 and 17.29 degrees; (e) said co-crystal is amodafinil:citric acid co-crystal and said X-ray diffraction patterncomprises peaks at 7.29 and 9.31 degrees; (f) said co-crystal is amodafinil:citric acid co-crystal and said X-ray diffraction patterncomprises peaks at 12.41 and 21.37 degrees; (g) said co-crystal is amodafinil:citric acid co-crystal and said X-ray diffraction patterncomprises a peak at 5.29 degrees; (h) said co-crystal is amodafinil:citric acid co-crystal and said X-ray diffraction patterncomprises a peak at 7.29 degrees; or (i) said co-crystal is amodafinil:citric acid co-crystal and said X-ray diffraction patterncomprises a peak at 12.41 degrees.
 14. The co-crystal according to claim8, wherein: (a) the co-crystal is characterized by a powder X-raydiffraction pattern comprising peaks expressed in terms of 2-thetaangles, wherein: (i) said co-crystal is a modafinil:succinic acidco-crystal and said X-ray diffraction pattern comprises peaks at 5.45,9.93, and 17.99 degrees; (ii) said co-crystal is a modafinil:succinicacid co-crystal and said X-ray diffraction pattern comprises peaks at19.95, 21.95, and 25.07 degrees; (iii) said co-crystal is amodafinil:succinic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.45, 17.99, and 21.35 degrees; (iv) said co-crystalis a modafinil:succinic acid co-crystal and said X-ray diffractionpattern comprises peaks at 5.45 and 9.93 degrees; (v) said co-crystal isa modafinil:succinic acid co-crystal and said X-ray diffraction patterncomprises peaks at 17.99 and 21.95 degrees; (vi) said co-crystal is amodafinil:succinic acid co-crystal and said X-ray diffraction patterncomprises peaks at 9.93 and 19.95 degrees; (vii) said co-crystal is amodafinil:succinic acid co-crystal and said X-ray diffraction patterncomprises a peak at 5.45 degrees; (viii) said co-crystal is amodafinil:succinic acid co-crystal and said X-ray diffraction patterncomprises a peak at 9.93 degrees; or (xi) said co-crystal is amodafinil:succinic acid co-crystal and said X-ray diffraction patterncomprises a peak at 17.99 degrees; or (b) the co-crystal ischaracterized by a DSC thermogram, wherein said co-crystal is amodafinil:succinic acid co-crystal and said DSC thermogram comprises anendothermic transition at about 149 degrees C.
 15. The co-crystalaccording to claim 8, wherein the co-crystal is characterized by apowder X-ray diffraction pattern comprising peaks expressed in terms of2-theta angles, wherein: (a) said co-crystal is a modafinil:DL-tartaricacid co-crystal and said X-ray diffraction pattern comprises peaks at4.75, 9.53, and 15.83 degrees; (b) said co-crystal is amodafinil:DL-tartaric acid co-crystal and said X-ray diffraction patterncomprises peaks at 17.61, 20.25, and 22.55 degrees; (c) said co-crystalis a modafinil:DL-tartaric acid co-crystal and said X-ray diffractionpattern comprises peaks at 10.07, 17.61, and 21.53 degrees; (d) saidco-crystal is a modafinil:DL-tartaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 4.75 and 15.83 degrees; (e) saidco-crystal is a modafinil:DL-tartaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 9.53 and 17.61 degrees; (f) saidco-crystal is a modafinil:DL-tartaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 21.53 and 22.55 degrees; (g) saidco-crystal is a modafinil:DL-tartaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 4.75 degrees; (h) saidco-crystal is a modafinil:DL-tartaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 9.53 degrees; or (i) saidco-crystal is a modafinil:DL-tartaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 15.83 degrees.
 16. Theco-crystal according to claim 8, wherein the co-crystal is characterizedby a powder X-ray diffraction pattern comprising peaks expressed interms of 2-theta angles, wherein: (a) said co-crystal is amodafinil:fumaric acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.45, 9.95, and 18.03 degrees; (b) said co-crystal isa modafinil:fumaric acid co-crystal and said X-ray diffraction patterncomprises peaks at 15.93, 18.81, and 21.95 degrees; (c) said co-crystalis a modafinil:fumaric acid co-crystal and said X-ray diffractionpattern comprises peaks at 9.95, 19.93, and 23.09 degrees; (d) saidco-crystal is a modafinil:fumaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 5.45 and 9.95 degrees; (e) saidco-crystal is a modafinil:fumaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 5.45 and 18.03 degrees; (f) saidco-crystal is a modafinil:fumaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 15.93 and 21.95 degrees; (g) saidco-crystal is a modafinil:fumaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 5.45 degrees; (h) saidco-crystal is a modafinil:fumaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 9.95 degrees; or (i) saidco-crystal is a modafinil:fumaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 18.03 degrees.
 17. Theco-crystal according to claim 16, wherein the co-crystal ismodafinil:fumaric acid Form I.
 18. The co-crystal according to claim 8,wherein the co-crystal is characterized by a powder X-ray diffractionpattern comprising peaks expressed in terms of 2-theta angles, wherein:(a) said co-crystal is a modafinil:fumaric acid co-crystal and saidX-ray diffraction pattern comprises peaks at 6.47, 8.57, and 9.99degrees; (b) said co-crystal is a modafinil:fumaric acid co-crystal andsaid X-ray diffraction pattern comprises peaks at 13.89, 14.53, and20.79 degrees; (c) said co-crystal is a modafinil:fumaric acidco-crystal and said X-ray diffraction pattern comprises peaks at 16.45,18.39, and 20.05 degrees; (d) said co-crystal is a modafinil:fumaricacid co-crystal and said X-ray diffraction pattern comprises peaks at6.47 and 20.79 degrees; (e) said co-crystal is a modafinil:fumaric acidco-crystal and said X-ray diffraction pattern comprises peaks at 9.99and 14.53 degrees; (f) said co-crystal is a modafinil:fumaric acidco-crystal and said X-ray diffraction pattern comprises peaks at 13.89and 20.05 degrees; (g) said co-crystal is a modafinil:fumaric acidco-crystal and said X-ray diffraction pattern comprises a peak at 6.47degrees; (h) said co-crystal is a modafinil:fumaric acid co-crystal andsaid X-ray diffraction pattern comprises a peak at 13.89 degrees; or (i)said co-crystal is a modafinil:fumaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 20.79 degrees.
 19. Theco-crystal according to claim 18, wherein the co-crystal ismodafinil:fumaric acid Form II.
 20. The co-crystal according to claim 8,wherein the co-crystal is characterized by a powder X-ray diffractionpattern comprising peaks expressed in terms of 2-theta angles, wherein:(a) said co-crystal is a modafinil:gentisic acid co-crystal and saidX-ray diffraction pattern comprises peaks at 6.96, 12.92, and 14.76degrees; (b) said co-crystal is a modafinil:gentisic acid co-crystal andsaid X-ray diffraction pattern comprises peaks at 14.76, 18.26, and20.10 degrees; (c) said co-crystal is a modafinil:gentisic acidco-crystal and said X-ray diffraction pattern comprises peaks at 6.96,17.40, and 20.94 degrees; (d) said co-crystal is a modafinil:gentisicacid co-crystal and said X-ray diffraction pattern comprises peaks at6.96 and 14.76 degrees; (e) said co-crystal is a modafinil:gentisic acidco-crystal and said X-ray diffraction pattern comprises peaks at 12.92and 17.40 degrees; (f) said co-crystal is a modafinil:gentisic acidco-crystal and said X-ray diffraction pattern comprises peaks at 6.96and 18.26 degrees; (g) said co-crystal is a modafinil:gentisic acidco-crystal and said X-ray diffraction pattern comprises a peak at 6.96degrees; (h) said co-crystal is a modafinil:gentisic acid co-crystal andsaid X-ray diffraction pattern comprises a peak at 14.76 degrees; or (i)said co-crystal is a modafinil:gentisic acid co-crystal and said X-raydiffraction pattern comprises a peak at 18.26 degrees.
 21. Theco-crystal according to claim 8, wherein the co-crystal is characterizedby a powder X-ray diffraction pattern comprising peaks expressed interms of 2-theta angles, wherein: (a) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.98, 17.54, and 19.68 degrees; (b) said co-crystalis a modafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 13.68, 14.80, and 21.12 degrees; (c) said co-crystalis a modafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 17.54, 19.68, and 21.86 degrees; (d) said co-crystalis a modafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.98 and 19.68 degrees; (e) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 13.68 and 14.80 degrees; (f) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.98 and 17.54 degrees; (g) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises a peak at 5.98 degrees; (h) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises a peak at 19.68 degrees; or (i) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises a peak at 17.54 degrees.
 22. The co-crystal according to claim8, wherein the co-crystal is characterized by a powder X-ray diffractionpattern comprising peaks expressed in terms of 2-theta angles, wherein:(a) said co-crystal is a modafinil:1-hydroxy-2-naphthoic acid co-crystaland said X-ray diffraction pattern comprises peaks at 5.72, 7.10, and14.16 degrees; (b) said co-crystal is a modafinil:1-hydroxy-2-naphthoicacid co-crystal and said X-ray diffraction pattern comprises peaks at11.48, 15.66, and 20.26 degrees; (c) said co-crystal is amodafinil:1-hydroxy-2-naphthoic acid co-crystal and said X-raydiffraction pattern comprises peaks at 5.72, 7.10, and 20.26 degrees;(d) said co-crystal is a modafinil:1-hydroxy-2-naphthoic acid co-crystaland said X-ray diffraction pattern comprises peaks at 5.72 and 7.10degrees; (e) said co-crystal is a modafinil:1-hydroxy-2-naphthoic acidco-crystal and said X-ray diffraction pattern comprises peaks at 14.16and 20.26 degrees; (f) said co-crystal is amodafinil:1-hydroxy-2-naphthoic acid co-crystal and said X-raydiffraction pattern comprises peaks at 5.72 and 14.16 degrees; (g) saidco-crystal is a modafinil:1-hydroxy-2-naphthoic acid co-crystal and saidX-ray diffraction pattern comprises a peak at 5.72 degrees; (h) saidco-crystal is a modafinil:1-hydroxy-2-naphthoic acid co-crystal and saidX-ray diffraction pattern comprises a peak at 7.10 degrees; or (i) saidco-crystal is a modafinil:1-hydroxy-2-naphthoic acid co-crystal and saidX-ray diffraction pattern comprises a peak at 14.16 degrees.
 23. Theco-crystal according to claim 8, wherein: (a) the co-crystal ischaracterized by a powder X-ray diffraction pattern comprising peaksexpressed in terms of 2-theta angles, wherein: (i) said co-crystal is amodafinil:malonic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.04, 9.26, and 16.73 degrees; (ii) said co-crystalis a modafinil:malonic acid co-crystal and said X-ray diffractionpattern comprises peaks at 18.23, 19.37, and 22.74 degrees; (iii) saidco-crystal is a modafinil:malonic acid co-crystal and said X-raydiffraction pattern comprises peaks at 5.04, 16.73, and 19.37 degrees;(iv) said co-crystal is a modafinil:malonic acid co-crystal and saidX-ray diffraction pattern comprises peaks at 5.04 and 9.26 degrees; (v)said co-crystal is a modafinil:malonic acid co-crystal and said X-raydiffraction pattern comprises peaks at 16.73 and 19.37 degrees; (vi)said co-crystal is a modafinil:malonic acid co-crystal and said X-raydiffraction pattern comprises peaks at 9.26 and 18.23 degrees; (vii)said co-crystal is a modafinil:malonic acid co-crystal and said X-raydiffraction pattern comprises a peak at 5.04 degrees; (viii) saidco-crystal is a modafinil:malonic acid co-crystal and said X-raydiffraction pattern comprises a peak at 9.26 degrees; or (ix) saidco-crystal is a modafinil:malonic acid co-crystal and said X-raydiffraction pattern comprises a peak at 19.37 degrees; or (b) theco-crystal is characterized by a DSC thermogram, wherein said co-crystalis a modafinil:malonic acid co-crystal and said DSC thermogram comprisesan endothermic transition at about 115 degrees C.
 24. The co-crystalaccording to claim 23, wherein the modafinil is R-(−)-modafinil.
 25. Theco-crystal according to claim 8, wherein: (a) the co-crystal ischaracterized by a powder X-ray diffraction pattern comprising peaksexpressed in terms of 2-theta angles, wherein: (i) said co-crystal is amodafinil:succinic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.36, 9.83, and 17.88 degrees; (ii) said co-crystalis a modafinil:succinic acid co-crystal and said X-ray diffractionpattern comprises peaks at 15.80, 19.87, and 21.85 degrees; (iii) saidco-crystal is a modafinil:succinic acid co-crystal and said X-raydiffraction pattern comprises peaks at 5.36, 9.83, and 21.85 degrees;(iv) said co-crystal is a modafinil:succinic acid co-crystal and saidX-ray diffraction pattern comprises peaks at 5.36 and 9.83 degrees; (v)said co-crystal is a modafinil:succinic acid co-crystal and said X-raydiffraction pattern comprises peaks at 17.88 and 19.87 degrees; (vi)said co-crystal is a modafinil:succinic acid co-crystal and said X-raydiffraction pattern comprises peaks at 9.83 and 15.80 degrees; (vii)said co-crystal is a modafinil:succinic acid co-crystal and said X-raydiffraction pattern comprises a peak at 5.36 degrees; (viii) saidco-crystal is a modafinil:succinic acid co-crystal and said X-raydiffraction pattern comprises a peak at 9.83 degrees; or (ix) saidco-crystal is a modafinil:succinic acid co-crystal and said X-raydiffraction pattern comprises a peak at 17.88 degrees; or (b) theco-crystal is characterized by a DSC thermogram, wherein said co-crystalis a modafinil:succinic acid co-crystal and said DSC thermogramcomprises an endothermic transition at about 145 degrees C.
 26. Theco-crystal according to claim 25, wherein the modafinil isR-(−)-modafinil.
 27. The co-crystal according to claim 8, wherein: (a)the co-crystal is characterized by a powder X-ray diffraction patterncomprising peaks expressed in terms of 2-theta angles, wherein: (i) saidco-crystal is a modafinil:citric acid co-crystal and said X-raydiffraction pattern comprises peaks at 5.18, 7.23, and 9.23 degrees;(ii) said co-crystal is a modafinil:citric acid co-crystal and saidX-ray diffraction pattern comprises peaks at 12.32, 13.23, and 17.25degrees; (iii) said co-crystal is a modafinil:citric acid co-crystal andsaid X-ray diffraction pattern comprises peaks at 9.23, 17.92, and 21.30degrees; (iv) said co-crystal is a modafinil:citric acid co-crystal andsaid X-ray diffraction pattern comprises peaks at 5.18 and 9.23 degrees;(v) said co-crystal is a modafinil:citric acid co-crystal and said X-raydiffraction pattern comprises peaks at 7.23 and 13.23 degrees; (vi) saidco-crystal is a modafinil:citric acid co-crystal and said X-raydiffraction pattern comprises peaks at 17.25 and 17.92 degrees; (vii)said co-crystal is a modafinil:citric acid co-crystal and said X-raydiffraction pattern comprises a peak at 5.18 degrees; (viii) saidco-crystal is a modafinil:citric acid co-crystal and said X-raydiffraction pattern comprises a peak at 7.23 degrees; or (ix) saidco-crystal is a modafinil:citric acid co-crystal and said X-raydiffraction pattern comprises a peak at 9.23 degrees; or (b) theco-crystal is characterized by a DSC thermogram, wherein said co-crystalis a modafinil:citric acid co-crystal and said DSC thermogram comprisesan endothermic transition at about 89 degrees C.
 28. The co-crystalaccording to claim 27, wherein the modafinil is R-(−)-modafinil.
 29. Theco-crystal according to claim 8, wherein the co-crystal is characterizedby a powder X-ray diffraction pattern comprising peaks expressed interms of 2-theta angles, wherein: (a) said co-crystal is amodafinil:1-hydroxy-2-naphthoic acid co-crystal and said X-raydiffraction pattern comprises peaks at 5.27, 8.85, and 10.60 degrees;(b) said co-crystal is a modafinil:1-hydroxy-2-naphthoic acid co-crystaland said X-ray diffraction pattern comprises peaks at 10.60, 14.47, and21.20 degrees; (c) said co-crystal is a modafinil:1-hydroxy-2-naphthoicacid co-crystal and said X-ray diffraction pattern comprises peaks at5.27, 14.47, and 23.03 degrees; (d) said co-crystal is amodafinil:1-hydroxy-2-naphthoic acid co-crystal and said X-raydiffraction pattern comprises peaks at 5.27 and 8.85 degrees; (e) saidco-crystal is a modafinil:1-hydroxy-2-naphthoic acid co-crystal and saidX-ray diffraction pattern comprises peaks at 10.60 and 23.03 degrees;(f) said co-crystal is a modafinil:1-hydroxy-2-naphthoic acid co-crystaland said X-ray diffraction pattern comprises peaks at 14.47 and 21.20degrees; (g) said co-crystal is a modafinil:1-hydroxy-2-naphthoic acidco-crystal and said X-ray diffraction pattern comprises a peak at 5.27degrees; (h) said co-crystal is a modafinil:1-hydroxy-2-naphthoic acidco-crystal and said X-ray diffraction pattern comprises a peak at 8.85degrees; or (i) said co-crystal is a modafinil:1-hydroxy-2-naphthoicacid co-crystal and said X-ray diffraction pattern comprises a peak at14.47 degrees.
 30. The co-crystal according to claim 29, wherein themodafinil is R-(−)-modafinil.
 31. The co-crystal according to claim 8,wherein the co-crystal is characterized by a powder X-ray diffractionpattern comprising peaks expressed in terms of 2-theta angles, wherein:(a) said co-crystal is a modafinil:DL-tartaric acid co-crystal and saidX-ray diffraction pattern comprises peaks at 4.67, 15.41, and 19.46degrees; (b) said co-crystal is a modafinil:DL-tartaric acid co-crystaland said X-ray diffraction pattern comprises peaks at 17.97, 19.46, and22.91 degrees; (c) said co-crystal is a modafinil:DL-tartaric acidco-crystal and said X-ray diffraction pattern comprises peaks at 4.67,22.91, and 24.63 degrees; (d) said co-crystal is a modafinil:DL-tartaricacid co-crystal and said X-ray diffraction pattern comprises peaks at4.67 and 19.46 degrees; (e) said co-crystal is a modafinil:DL-tartaricacid co-crystal and said X-ray diffraction pattern comprises peaks at17.97 and 22.91 degrees; (f) said co-crystal is a modafinil:DL-tartaricacid co-crystal and said X-ray diffraction pattern comprises peaks at15.41 and 24.63 degrees; (g) said co-crystal is a modafinil:DL-tartaricacid co-crystal and said X-ray diffraction pattern comprises a peak at4.67 degrees; (h) said co-crystal is a modafinil:DL-tartaric acidco-crystal and said X-ray diffraction pattern comprises a peak at 19.46degrees; or (i) said co-crystal is a modafinil:DL-tartaric acidco-crystal and said X-ray diffraction pattern comprises a peak at 22.91degrees.
 32. The co-crystal according to claim 31, wherein the modafinilis R-(−)-modafinil.
 33. The co-crystal according to claim 8, wherein theco-crystal is characterized by a powder X-ray diffraction patterncomprising peaks expressed in terms of 2-theta angles, wherein: (a) saidco-crystal is a modafinil:orotic acid co-crystal and said X-raydiffraction pattern comprises peaks at 9.77, 17.85, and 20.52 degrees;(b) said co-crystal is a modafinil:orotic acid co-crystal and said X-raydiffraction pattern comprises peaks at 17.85, 24.03, and 26.80 degrees;(c) said co-crystal is a modafinil:orotic acid co-crystal and said X-raydiffraction pattern comprises peaks at 9.77, 20.52, and 24.03 degrees;(d) said co-crystal is a modafinil:orotic acid co-crystal and said X-raydiffraction pattern comprises peaks at 9.77 and 17.85 degrees; (e) saidco-crystal is a modafinil:orotic acid co-crystal and said X-raydiffraction pattern comprises peaks at 17.85 and 24.03 degrees; (f) saidco-crystal is a modafinil:orotic acid co-crystal and said X-raydiffraction pattern comprises peaks at 9.77 and 26.80 degrees; (g) saidco-crystal is a modafinil:orotic acid co-crystal and said X-raydiffraction pattern comprises a peak at 9.77 degrees; (h) saidco-crystal is a modafinil:orotic acid co-crystal and said X-raydiffraction pattern comprises a peak at 17.85 degrees; or (i) saidco-crystal is a modafinil:orotic acid co-crystal and said X-raydiffraction pattern comprises a peak at 24.03 degrees.
 34. Theco-crystal according to claim 33, wherein the modafinil isR-(−)-modafinil.
 35. The pharmaceutical composition of claim 86 whereinthe composition is a solvate form and is characterized by a powder X-raydiffraction pattern comprising peaks expressed in terms of 2-thetaangles, wherein: (a) said form is a modafinil acetic acid solvate andsaid X-ray diffraction pattern comprises peaks at 6.17, 9.63, and 19.99degrees; (b) said form is a modafinil acetic acid solvate and said X-raydiffraction pattern comprises peaks at 6.17 and 9.63 degrees; (c) saidform is a modafinil acetic acid solvate and said X-ray diffractionpattern comprises peaks at 19.99 and 21.83 degrees; (d) said form is amodafinil acetic acid solvate and said X-ray diffraction patterncomprises peaks at 9.63 and 19.99 degrees; or (e) said form is amodafinil acetic acid solvate and said X-ray diffraction patterncomprises a peak at 6.17 degrees.
 36. The pharmaceutical composition ofclaim 86 wherein the composition is a solvate form and is characterizedby a powder X-ray diffraction pattern comprising peaks expressed interms of 2-theta angles, wherein: (a) said form is a modafiniltetrahydrofuran solvate and said X-ray diffraction pattern comprisespeaks at 6.97, 9.79, and 10.97 degrees; (b) said form is a modafiniltetrahydrofuran solvate and said X-ray diffraction pattern comprisespeaks at 10.97 and 20.59 degrees; (c) said form is a modafiniltetrahydrofuran solvate and said X-ray diffraction pattern comprisespeaks at 9.79 and 19.03 degrees; (d) said form is a modafiniltetrahydrofuran solvate and said X-ray diffraction pattern comprisespeaks at 6.97 and 16.19 degrees; or (e) said form is a modafiniltetrahydrofuran solvate and said X-ray diffraction pattern comprises apeak at 6.97 degrees.
 37. The pharmaceutical composition of claim 86wherein the composition is a solvate form and is characterized by apowder X-ray diffraction pattern comprising peaks expressed in terms of2-theta angles, wherein: (a) said form is a modafinil 1,4-dioxanesolvate and said X-ray diffraction pattern comprises peaks at 6.93,9.85, and 10.97 degrees; (b) said form is a modafinil 1,4-dioxanesolvate and said X-ray diffraction pattern comprises peaks at 6.93 and20.65 degrees; (c) said form is a modafinil 1,4-dioxane solvate and saidX-ray diffraction pattern comprises peaks at 10.97 and 18.97 degrees;(d) said form is a modafinil 1,4-dioxane solvate and said X-raydiffraction pattern comprises peaks at 16.19 and 23.33 degrees; or (e)said form is a modafinil 1,4-dioxane solvate and said X-ray diffractionpattern comprises a peak at 6.93 degrees.
 38. The pharmaceuticalcomposition of claim 86 wherein the composition is a solvate form and ischaracterized by a powder X-ray diffraction pattern comprising peaksexpressed in terms of 2-theta angles, wherein: (a) said form is amodafinil methanol solvate and said X-ray diffraction pattern comprisespeaks at 6.15, 9.89, and 20.07 degrees; (b) said form is a modafinilmethanol solvate and said X-ray diffraction pattern comprises peaks at6.15 and 9.89 degrees; (c) said form is a modafinil methanol solvate andsaid X-ray diffraction pattern comprises peaks at 12.25 and 17.97degrees; (d) said form is a modafinil methanol solvate and said X-raydiffraction pattern comprises peaks at 20.07 and 21.85 degrees; or (e)said form is a modafinil methanol solvate and said X-ray diffractionpattern comprises a peak at 6.15 degrees.
 39. The pharmaceuticalcomposition of claim 86 wherein the composition is a solvate form and ischaracterized by a powder X-ray diffraction pattern comprising peaksexpressed in terms of 2-theta angles, wherein: (a) said form is amodafinil nitromethane solvate and said X-ray diffraction patterncomprises peaks at 6.17, 9.77, and 20.07 degrees; (b) said form is amodafinil nitromethane solvate and said X-ray diffraction patterncomprises peaks at 12.29 and 15.89 degrees; (c) said form is a modafinilnitromethane solvate and said X-ray diffraction pattern comprises peaksat 6.17 and 20.07 degrees; (d) said form is a modafinil nitromethanesolvate and said X-ray diffraction pattern comprises peaks at 9.77 and22.17 degrees; or (e) said form is a modafinil nitromethane solvate andsaid X-ray diffraction pattern comprises a peak at 6.17 degrees.
 40. Thepharmaceutical composition of claim 86 wherein the composition is asolvate form and is characterized by a powder X-ray diffraction patterncomprising peaks expressed in terms of 2-theta angles, wherein: (a) saidform is a modafinil acetone solvate and said X-ray diffraction patterncomprises peaks at 6.11, 9.53, and 15.81 degrees; (b) said form is amodafinil acetone solvate and said X-ray diffraction pattern comprisespeaks at 6.11 and 9.53 degrees; (c) said form is a modafinil acetonesolvate and said X-ray diffraction pattern comprises peaks at 15.81 and20.03 degrees; (d) said form is a modafinil acetone solvate and saidX-ray diffraction pattern comprises peaks at 18.11 and 21.63 degrees; or(e) said form is a modafinil acetone solvate and said X-ray diffractionpattern comprises a peak at 6.11 degrees. 41.-45. (canceled)
 46. Theco-crystal of claim 1, wherein the modafinil is R-(−)-modafinil.
 47. Theco-crystal of claim 1, wherein the modafinil is S-(+)-modafinil.
 48. Theco-crystal of claim 8, wherein the modafinil is R-(−)-modafinil.
 49. Theco-crystal of claim 8, wherein the modafinil is S-(+)-modafinil. 50.-69.(canceled)
 70. A method for treating a subject suffering from excessivedaytime sleepiness associated with narcolepsy, multiple sclerosisrelated fatigue, infertility, eating disorders, attention deficithyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleepapnea, or myopathies, which comprises administering to a subject atherapeutically effective amount of a co-crystal comprising modafinil.71. The method according to claim 70, wherein the subject is a humansubject.
 72. The pharmaceutical composition of claim 86 wherein thecomposition is a solvate form and is characterized by a powder X-raydiffraction pattern comprising peaks expressed in terms of 2-thetaangles, wherein: (a) said form is a R-(−)-modafinil benzyl alcoholsolvate and said X-ray diffraction pattern comprises peaks at 7.76,18.57, and 21.53 degrees; (b) said form is a R-(−)-modafinil benzylalcohol solvate and said X-ray diffraction pattern comprises peaks at5.77 and 7.76 degrees; (c) said form is a R-(−)-modafinil benzyl alcoholsolvate and said X-ray diffraction pattern comprises peaks at 18.57 and21.53 degrees; (d) said form is a R-(−)-modafinil benzyl alcohol solvateand said X-ray diffraction pattern comprises peaks at 10.48 and 27.73degrees; or (e) said form is a R-(−)-modafinil benzyl alcohol solvateand said X-ray diffraction pattern comprises a peak at 7.76 degrees. 73.The pharmaceutical composition of claim 86 wherein the composition is asolvate form and is characterized by a powder X-ray diffraction patterncomprising peaks expressed in terms of 2-theta angles, wherein: (a) saidform is a R-(−)-modafinil isopropanol solvate and said X-ray diffractionpattern comprises peaks at 5.76, 7.77, and 21.53 degrees; (b) said formis a R-(−)-modafinil isopropanol solvate and said X-ray diffractionpattern comprises peaks at 10.49 and 18.58 degrees; (c) said form is aR-(−)-modafinil isopropanol solvate and said X-ray diffraction patterncomprises peaks at 7.77 and 18.58 degrees; (d) said form is aR-(−)-modafinil isopropanol solvate and said X-ray diffraction patterncomprises peaks at 5.76 and 15.79 degrees; or (e) said form is aR-(−)-modafinil isopropanol solvate and said X-ray diffraction patterncomprises a peak at 7.77 degrees.
 74. The pharmaceutical composition ofclaim 86 wherein the composition is a solvate form and is characterizedby a powder X-ray diffraction pattern comprising peaks expressed interms of 2-theta angles, wherein: (a) said form is a R-(−)-modafinilacetonitrile solvate and said X-ray diffraction pattern comprises peaksat 6.17, 8.16, and 21.86 degrees; (b) said form is a R-(−)-modafinilacetonitrile solvate and said X-ray diffraction pattern comprises peaksat 6.17 and 11.19 degrees; (c) said form is a R-(−)-modafinilacetonitrile solvate and said X-ray diffraction pattern comprises peaksat 8.16 and 10.19 degrees; (d) said form is a R-(−)-modafinilacetonitrile solvate and said X-ray diffraction pattern comprises peaksat 6.17 and 8.16 degrees; or (e) said form is a R-(−)-modafinilacetonitrile solvate and said X-ray diffraction pattern comprises a peakat 6.17 degrees.
 75. The pharmaceutical composition of claim 86 whereinthe composition is a solvate form and is characterized by a powder X-raydiffraction pattern comprising peaks expressed in terms of 2-thetaangles, wherein: (a) said form is a R-(−)-modafinil ethanol solvate andsaid X-ray diffraction pattern comprises peaks at 6.13, 9.59, and 20.05degrees; (b) said form is a R-(−)-modafinil ethanol solvate and saidX-ray diffraction pattern comprises peaks at 15.69 and 21.55 degrees;(c) said form is a R-(−)-modafinil ethanol solvate and said X-raydiffraction pattern comprises peaks at 9.59 and 20.05 degrees; (d) saidform is a R-(−)-modafinil ethanol solvate and said X-ray diffractionpattern comprises peaks at 6.13 and 15.69 degrees; or (e) said form is aR-(−)-modafinil ethanol solvate and said X-ray diffraction patterncomprises a peak at 6.13 degrees.
 76. The co-crystal according to claim8, wherein the co-crystal is characterized by a powder X-ray diffractionpattern comprising peaks expressed in terms of 2-theta angles, wherein:(a) said co-crystal is a modafinil:gentisic acid co-crystal and saidX-ray diffraction pattern comprises peaks at 7.07, 9.07, and 12.31degrees; (b) said co-crystal is a modafinil-gentisic acid co-crystal andsaid X-ray diffraction pattern comprises peaks at 9.07, 18.39, and 21.27degrees; (c) said co-crystal is a modafinil:gentisic acid co-crystal andsaid X-ray diffraction pattern comprises peaks at 17.63, 23.57, and26.93 degrees; (d) said co-crystal is a modafinil:gentisic acidco-crystal and said X-ray diffraction pattern comprises peaks at 9.07and 16.03 degrees; (e) said co-crystal is a modafinil:gentisic acidco-crystal and said X-ray diffraction pattern comprises peaks at 7.51and 21.27 degrees; (f) said co-crystal is a modafinil:gentisic acidco-crystal and said X-ray diffraction pattern comprises peaks at 7.07and 7.51 degrees; (g) said co-crystal is a modafinil:gentisic acidco-crystal and said X-ray diffraction pattern comprises a peak at 9.07degrees; (h) said co-crystal is a modafinil:gentisic acid co-crystal andsaid X-ray diffraction pattern comprises a peak at 7.07 degrees; (i)said co-crystal is a modafinil:gentisic acid co-crystal and said X-raydiffraction pattern comprises a peak at 16.03 degrees; (j) saidco-crystal is a modafinil:gentisic acid co-crystal and said X-raydiffraction pattern comprises peaks at 7.07, 9.07, 16.03, 18.39, 21.27,and 23.57 degrees; or (k) said co-crystal is a modafinil:gentisic acidco-crystal and said X-ray diffraction pattern comprises peaks at 7.51,12.31, 14.09, 16.03, 17.63, and 23.57 degrees.
 77. The co-crystalaccording to claim 8, wherein the co-crystal is characterized by apowder X-ray diffraction pattern comprising peaks expressed in terms of2-theta angles, wherein: (a) said co-crystal is a modafinil:glutaricacid co-crystal and said X-ray diffraction pattern comprises peaks at9.78, 18.92, and 21.36 degrees; (b) said co-crystal is amodafinil:glutaric acid co-crystal and said X-ray diffraction patterncomprises peaks at 20.50, 22.25, and 23.87 degrees; (c) said co-crystalis a modafinil:glutaric acid co-crystal and said X-ray diffractionpattern comprises peaks at 8.67, 19.74, and 27.16 degrees; (d) saidco-crystal is a modafinil:glutaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 8.67 and 18.92 degrees; (e) saidco-crystal is a modafinil:glutaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 9.78 and 20.50 degrees; (f) saidco-crystal is a modafinil:glutaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 21.36 and 23.87 degrees; (g) saidco-crystal is a modafinil:glutaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 23.87 degrees; (h) saidco-crystal is a modafinil:glutaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 8.67 degrees; (i) saidco-crystal is a modafinil:glutaric acid co-crystal and said X-raydiffraction pattern comprises a peak at 9.78 degrees; (j) saidco-crystal is a modafinil:glutaric acid co-crystal and said X-raydiffraction pattern comprises peaks at 8.67, 9.78, 18.92, 20.50, and23.87 degrees; or (k) said co-crystal is a modafinil:glutaric acidco-crystal and said X-ray diffraction pattern comprises peaks at 18.92,20.50, 21.36, 22.25, and 23.87 degrees.
 78. The co-crystal according toclaim 8, wherein the co-crystal is characterized by a powder X-raydiffraction pattern comprising peaks expressed in terms of 2-thetaangles, wherein: (a) said co-crystal is a modafinil:citric acidco-crystal and said X-ray diffraction pattern comprises peaks at 7.06,9.10, and 17.95 degrees; (b) said co-crystal is a modafinil:citric acidco-crystal and said X-ray diffraction pattern comprises peaks at 12.43,13.18, and 20.85 degrees; (c) said co-crystal is a modafinil:citric acidco-crystal and said X-ray diffraction pattern comprises peaks at 5.23,7.06, and 9.10 degrees; (d) said co-crystal is a modafinil:citric acidco-crystal and said X-ray diffraction pattern comprises peaks at 5.23and 12.43 degrees; (e) said co-crystal is a modafinil:citric acidco-crystal and said X-ray diffraction pattern comprises peaks at 9.10and 17.95 degrees; (f) said co-crystal is a modafinil:citric acidco-crystal and said X-ray diffraction pattern comprises peaks at 9.10and 12.43 degrees; (g) said co-crystal is a modafinil:citric acidco-crystal and said X-ray diffraction pattern comprises a peak at 7.06degrees; (h) said co-crystal is a modafinil:citric acid co-crystal andsaid X-ray diffraction pattern comprises a peak at 9.10 degrees; (i)said co-crystal is a modafinil:citric acid co-crystal and said X-raydiffraction pattern comprises a peak at 17.95 degrees; (j) saidco-crystal is a modafinil:citric acid co-crystal and said X-raydiffraction pattern comprises peaks at 7.06, 12.43, 13.18, 17.95, and20.85 degrees; or (k) said co-crystal is a modafinil:citric acidco-crystal and said X-ray diffraction pattern comprises peaks at 7.06,9.10, 17.95, 21.39, and 22.96 degrees.
 79. The co-crystal according toclaim 8, wherein the co-crystal is characterized by a powder X-raydiffraction pattern comprising peaks expressed in terms of 2-thetaangles, wherein: (a) said co-crystal is a modafinil:L-tartaric acidco-crystal and said X-ray diffraction pattern comprises peaks at 4.56,10.33, and 17.29 degrees; (b) said co-crystal is a modafinil:L-tartaricacid co-crystal and said X-ray diffraction pattern comprises peaks at17.29, 19.91, and 21.13 degrees; (c) said co-crystal is amodafinil:L-tartaric acid co-crystal and said X-ray diffraction patterncomprises peaks at 4.56, 14.45, and 19.91 degrees; (d) said co-crystalis a modafinil:L-tartaric acid co-crystal and said X-ray diffractionpattern comprises peaks at 4.56 and 10.33 degrees; (e) said co-crystalis a modafinil:L-tartaric acid co-crystal and said X-ray diffractionpattern comprises peaks at 17.29 and 19.91 degrees; (f) said co-crystalis a modafinil:L-tartaric acid co-crystal and said X-ray diffractionpattern comprises peaks at 19.91 and 21.13 degrees; (g) said co-crystalis a modafinil:L-tartaric acid co-crystal and said X-ray diffractionpattern comprises a peak at 4.56 degrees; (h) said co-crystal is amodafinil:L-tartaric acid co-crystal and said X-ray diffraction patterncomprises a peak at 10.33 degrees; (i) said co-crystal is amodafinil:L-tartaric acid co-crystal and said X-ray diffraction patterncomprises a peak at 19.91 degrees; or (j) said co-crystal is amodafinil:L-tartaric acid co-crystal and said X-ray diffraction patterncomprises peaks at 4.56, 10.33, 17.29, 19.91, and 21.13 degrees.
 80. Theco-crystal according to claim 8, wherein the co-crystal is characterizedby a powder X-ray diffraction pattern comprising peaks expressed interms of 2-theta angles, wherein: (a) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.99, 14.73, and 17.38 degrees; (b) said co-crystalis a modafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 17.38, 18.64, and 28.85 degrees; (c) said co-crystalis a modafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 14.73, 18.64, and 25.66 degrees; (d) said co-crystalis a modafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.99 and 14.73 degrees; (e) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 17.38 and 18.64 degrees; (f) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.99 and 28.85 degrees; (g) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises a peak at 5.99 degrees; (h) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises a peak at 14.73 degrees; (i) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises a peak at 28.85 degrees; or (j) said co-crystal is amodafinil:oxalic acid co-crystal and said X-ray diffraction patterncomprises peaks at 5.99, 14.73, 17.38, 18.64, and 28.85 degrees.
 81. Theco-crystal according to claim 8, wherein the co-crystal is characterizedby a powder X-ray diffraction pattern comprising peaks expressed interms of 2-theta angles, wherein: (a) said co-crystal is amodafinil:palmitic acid co-crystal and said X-ray diffraction patterncomprises peaks at 3.80, 6.55, and 7.66 degrees; (b) said co-crystal isa modafinil:palmitic acid co-crystal and said X-ray diffraction patterncomprises peaks at 10.24, 19.48, and 21.09 degrees; (c) said co-crystalis a modafinil:palmitic acid co-crystal and said X-ray diffractionpattern comprises peaks at 3.80, 19.48, and 23.99 degrees; (d) saidco-crystal is a modafinil:palmitic acid co-crystal and said X-raydiffraction pattern comprises peaks at 3.80 and 6.55 degrees; (e) saidco-crystal is a modafinil:palmitic acid co-crystal and said X-raydiffraction pattern comprises peaks at 6.55 and 7.66 degrees; (f) saidco-crystal is a modafinil:palmitic acid co-crystal and said X-raydiffraction pattern comprises peaks at 19.48 and 23.99 degrees; (g) saidco-crystal is a modafinil:palmitic acid co-crystal and said X-raydiffraction pattern comprises a peak at 3.80 degrees; (h) saidco-crystal is a modafinil:palmitic acid co-crystal and said X-raydiffraction pattern comprises a peak at 6.55 degrees; (i) saidco-crystal is a modafinil:palmitic acid co-crystal and said X-raydiffraction pattern comprises a peak at 7.66 degrees; (j) saidco-crystal is a modafinil:palmitic acid co-crystal and said X-raydiffraction pattern comprises peaks at 3.80, 7.66, 10.24, and 19.48degrees; or (k) said co-crystal is a modafinil:palmitic acid co-crystaland said X-ray diffraction pattern comprises peaks at 3.80, 6.55, 7.66,10.24, 19.48, and 23.99 degrees.
 82. The co-crystal according to claim8, wherein the co-crystal is characterized by a powder X-ray diffractionpattern comprising peaks expressed in terms of 2-theta angles, wherein:(a) said co-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises peaks at 6.52, 8.53, and 10.25 degrees;(b) said co-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises peaks at 19.06, 22.75, and 25.08 degrees;(c) said co-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises peaks at 6.52, 10.25, and 19.06 degrees;(d) said co-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises peaks at 6.52 and 8.53 degrees; (e) saidco-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises peaks at 6.52 and 10.25 degrees; (f) saidco-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises peaks at 19.06 and 22.29 degrees; (g) saidco-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises a peak at 6.52 degrees; (h) saidco-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises a peak at 8.53 degrees; (i) saidco-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises a peak at 19.06 degrees; (j) saidco-crystal is a modafinil:L-proline co-crystal and said X-raydiffraction pattern comprises peaks at 6.52, 10.25, 19.06, 22.75, and25.08 degrees; or (k) said co-crystal is a modafinil:L-prolineco-crystal and said X-ray diffraction pattern comprises peaks at 8.53,10.25, 19.06, 22.29, and 25.08 degrees.
 83. The co-crystal according toclaim 8, wherein the co-crystal is characterized by a powder X-raydiffraction pattern comprising peaks expressed in terms of 2-thetaangles, wherein: (a) said co-crystal is a modafinil:salicylic acidco-crystal and said X-ray diffraction pattern comprises peaks at 8.92,10.85, and 17.07 degrees; (b) said co-crystal is a modafinil:salicylicacid co-crystal and said X-ray diffraction pattern comprises peaks at12.18, 21.24, and 23.32 degrees; (c) said co-crystal is amodafinil:salicylic acid co-crystal and said X-ray diffraction patterncomprises peaks at 8.92, 18.81, and 25.22 degrees; (d) said co-crystalis a modafinil:salicylic acid co-crystal and said X-ray diffractionpattern comprises peaks at 8.92 and 10.85 degrees; (e) said co-crystalis a modafinil:salicylic acid co-crystal and said X-ray diffractionpattern comprises peaks at 17.07 and 21.24 degrees; (f) said co-crystalis a modafinil:salicylic acid co-crystal and said X-ray diffractionpattern comprises peaks at 23.32 and 25.22 degrees; (g) said co-crystalis a modafinil:salicylic acid co-crystal and said X-ray diffractionpattern comprises a peak at 8.92 degrees; (h) said co-crystal is amodafinil:salicylic acid co-crystal and said X-ray diffraction patterncomprises a peak at 10.85 degrees; (i) said co-crystal is amodafinil:salicylic acid co-crystal and said X-ray diffraction patterncomprises a peak at 21.24 degrees; (j) said co-crystal is amodafinil:salicylic acid co-crystal and said X-ray diffraction patterncomprises peaks at 8.92, 12.18, 17.07, 21.24, and 23.32 degrees; or (k)said co-crystal is a modafinil:salicylic acid co-crystal and said X-raydiffraction pattern comprises peaks at 10.85, 14.04, 21.24, and 23.32degrees.
 84. The co-crystal according to claim 8, wherein the co-crystalis characterized by a powder X-ray diffraction pattern comprising peaksexpressed in terms of 2-theta angles, wherein: (a) said co-crystal is amodafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises peaks at 3.12, 6.55, and 10.24 degrees; (b) said co-crystal isa modafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises peaks at 6.55, 13.97, and 17.62 degrees; (c) said co-crystalis a modafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises peaks at 3.12, 21.38, and 23.81 degrees; (d) said co-crystalis a modafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises peaks at 3.12 and 6.55 degrees; (e) said co-crystal is amodafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises peaks at 10.24 and 17.62 degrees; (f) said co-crystal is amodafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises peaks at 21.38 and 23.81 degrees; (g) said co-crystal is amodafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises a peak at 3.12 degrees; (h) said co-crystal is amodafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises a peak at 6.55 degrees; (i) said co-crystal is amodafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises a peak at 21.38 degrees; (j) said co-crystal is amodafinil:lauric acid co-crystal and said X-ray diffraction patterncomprises peaks at 3.12, 10.24, 16.40, 19.02, and 21.38 degrees; or (k)said co-crystal is a modafinil:lauric acid co-crystal and said X-raydiffraction pattern comprises peaks at 3.12, 6.55, 10.24, 21.38, and23.81 degrees.
 85. The co-crystal according to claim 8, wherein theco-crystal is characterized by a powder X-ray diffraction patterncomprising peaks expressed in terms of 2-theta angles, wherein: (a) saidco-crystal is a modafinil:L-malic acid co-crystal and said X-raydiffraction pattern comprises peaks at 4.62, 9.32, and 19.30 degrees;(b) said co-crystal is a modafinil:L-malic acid co-crystal and saidX-ray diffraction pattern comprises peaks at 9.32, 10.32, and 21.48degrees; (c) said co-crystal is a modafinil:L-malic acid co-crystal andsaid X-ray diffraction pattern comprises peaks at 19.30, 21.48, and24.26 degrees; (d) said co-crystal is a modafinil:L-malic acidco-crystal and said X-ray diffraction pattern comprises peaks at 4.62and 9.32 degrees; (e) said co-crystal is a modafinil:L-malic acidco-crystal and said X-ray diffraction pattern comprises peaks at 9.32and 10.32 degrees; (f) said co-crystal is a modafinil:L-malic acidco-crystal and said X-ray diffraction pattern comprises peaks at 19.30and 21.48 degrees; (g) said co-crystal is a modafinil:L-malic acidco-crystal and said X-ray diffraction pattern comprises a peak at 4.62degrees; (h) said co-crystal is a modafinil:L-malic acid co-crystal andsaid X-ray diffraction pattern comprises a peak at 9.32 degrees; (i)said co-crystal is a modafinil:L-malic acid co-crystal and said X-raydiffraction pattern comprises a peak at 19.30 degrees; (j) saidco-crystal is a modafinil:L-malic acid co-crystal and said X-raydiffraction pattern comprises peaks at 4.62, 15.83, 17.38, 19.30, and21.48 degrees; or (k) said co-crystal is a modafinil:L-malic acidco-crystal and said X-ray diffraction pattern comprises peaks at 9.32,10.32, 17.38, 19.30, 21.48, and 24.26 degrees.
 86. A pharmaceuticalcomposition comprising a modafinil solvate wherein the solvent isselected from the group consisting of: acetic acid, tetrahydrofuran,1,4-dioxane, methanol, nitromethane, acetone, o-xylene, benzene,ethanol, benzyl alcohol, isopropanol, acetonitrile, and toluene. 87.Form VII modafinil as characterized by a powder X-ray diffractionpattern comprising peaks expressed in terms of 2-theta angles,characterized by any one, any two, any three, any four, any five, or anysix or more of the peaks in FIG. 48 including, but not limited to, 5.47,9.99, 15.73, 17.85, 18.77, 20.05, 21.23, 22.05, 23.15, and 25.13degrees.